Pyrimidinyl cephalosporanic acid derivatives and pharmaceutical compositions

ABSTRACT

This invention relates to novel 7-pyrimidinyl and pyridinyl acetamido cephem derivatives of high antibacterial activity.

This application is a division of application Ser. No. 032,778, filedApr. 24, 1979, U.S. Pat. No. 4,267,176, which is a continuation-in-partof application Ser. No. 960,226, filed Nov. 13, 1978, now abandoned.

The present invention relates to novel cephalosporanic acid derivativesand pharmaceutically acceptable salts thereof. More particularly, itrelates to novel cephalosporanic acid derivatives and pharmaceuticallyacceptable salts thereof, which have anti-bacterial activities, toprocesses for the preparation thereof, to pharmaceutical compositioncomprising the same, and to a method of using the same therapeuticallyin the treatment of infectious diseases in human beings and animals.

Accordingly, one object of the present invention is to provide novelcephalosporanic acid derivatives and pharmaceutically acceptable saltsthereof, which are highly active against a number of pathogenicbacteria.

Another object of the present invention is to provide processes for thepreparation of novel cephalosporanic acid derivatives andpharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as an active ingredient, said cephalosporanicacid derivatives or its pharmaceutically acceptable salts.

Still further object of the present invention is to provide a method forthe treatment of infectious diseases by pathogenic bacteria in humanbeings and animals.

The object cephalosporanic acid derivatives can be represented by thefollowing general formula (I): ##STR1## wherein R¹ is a group of theformula: ##STR2## in which R_(a) ¹ is hydrogen, amino or a protectedamino group,

R_(b) ¹ and R_(c) ¹ are each hydrogen, halogen, lower alkoxy orarylthio, and

Z is N or CH,

R² is hydrogen or lower alkoxy,

R³ is hydrogen or lower alkyl,

R⁴ is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, lower alkoxy,lower alkanoyloxymethyl, lower alkanoylthiomethyl, orheterocyclic-thiomethyl which may have suitable substituent(s),

R⁵ is carboxy or its derivative, and

X is lower alkylene or a group of the formula: ##STR3## in which R⁶ ishydrogen or an organic residue which may have suitable substituent(s),and non-toxic, pharmaceutically acceptable salts thereof.

In the object compounds (I) and the corresponding starting compounds(III) of Process I mentioned below, the partial structure represented bythe formula: ##STR4## is to be understood to include both of thegeometrical structures represented by the formula: ##STR5##

Accordingly, with regard to the compounds having the above mentionedpartial structure, the compounds having the geometrical structure shownby the formula (A) are referred to as "syn isomer" and the othercompounds having the alternative one shown by the formula (A') as "antiisomer" in this specification.

Suitable pharmaceutically acceptable salts of the object compounds (I)are conventional non-toxic salts and may include an inorganic salt, forexample, a metal salt such as an alkali metal salt (e.g., sodium salt,potassium salt, etc.) and an alkaline earth metal salt (e.g., calciumsalt, magnesium salt, etc.), and an ammonium salt etc.; an organic salt,for example, an organic amine salt (e.g., trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt, etc.) etc.; an organic carboxylicor sulfonic acid addition salt (e.g., formate, acetate, maleate,tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.);an inorganic acid addition salt (e.g., hydrochloride, hydrobromide,sulfate, phosphate, etc.); a salt with a basic or acidic amino acid(e.g., arginine, aspartic acid, glutamic acid, etc.), and the like.

According to the present invention, the object compounds (I) and thepharmaceutically acceptable salts thereof can be prepared by theprocesses as illustrated by the following schemes. ##STR6##

Some of the starting compounds (III) in Process I are novel and can beprepared, for example, from the known compounds (A-1), (B-1), (C-1a) and(D-1a) by the Processes A to Q as illustrated by the following reactionschemes or a similar manner thereto.

The compounds (A-1), (B-1), (C-1a) and (D-1a) are disclosed, forexample, in the following literatures.

    ______________________________________                                        Compound (A-1):                                                                ##STR7##          (Journal of Organic Chemistry, Vol.27, page 3608)            Compound (B-1):                                                              ##STR8##          (Journal of the American Chemical Society, Vol.69,                            page 2657 (1949)).                                           Compound (C-1a):                                                             ##STR9##          (Chemical Abstract Vol.54, 6709)                            ##STR10##         (Chemical Abstract Vol.52, 7313g)                           ##STR11##         (Chemical Abstract Vol.53, 7162c)                           ##STR12##         (Journal fur Praktische Chemie Reihe 4, Vol.13, page                          58, 1961)                                                    Compound (D-1a)                                                              ##STR13##         (Abstracts of the 9th Congress of Heterocyclic                                Chemistry, page 146, Fukuoka, Japan,                       ______________________________________                                                           1976)                                                       ##STR14##

In the above and subsequent description of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term "lower" is intended to mean a group having 1 to 6 carbon atoms,unless otherwise provided.

Suitable "protective group" in the terms "a protected amino group" and"a protected amino(lower)alkyl group" may include an acyl and the otherconventional protective group such as ar(lower)alkyl (e.g., benzyl,trityl, diphenylmethyl, etc.), substituted phenylthio (e.g.2-nitrophenylthio, etc.), substituted aralkylidene (e.g.4-nitrobenzylidene, etc.), substituted alkylidene (e.g.1-methoxycarbonyl-2-propylidene, etc.), substituted lowercycloalkylidene (e.g. 2-ethoxycarbonylcyclohexylidene, etc.), and thelike. And suitable acyl group may be the ones derived from carboxylic,sulfonic or carbamic acid, and more particularly substituted orunsubstituted carbamoyl, aliphatic acyl, and acyl having an aromaticring (referred to as aromatic acyl) or heterocyclic ring (referred to asheterocyclic acyl.)

Suitable examples of the aliphatic acyl may be lower alkanoyl (e.g.,formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, oxalyl,succinyl, pivaloyl, etc.); lower cycloalkanecarbonyl (e.g.cyclopentanecarbonyl, cyclohexanecarbonyl, etc.);

lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl,hexyloxycarbonyl, etc.); lower cycloalkyl(lower)alkoxycarbonyl (e.g.,1-cyclopropylethoxycarbony, etc.); lower alkoxyalkanol (e.g.,methoxyacetyl, ethoxyacetyl, methoxypropionyl, etc.); and

lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,butanesulfonyl, etc.).

Suitable examples of the aromatic acyl may be ar(lower)alkanoyl (e.g.,phenylacetyl, phenylpropionyl, etc.); ar(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.);

arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); and aroyl (e.g.,benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.).

Suitable examles of the heterocyclic acyl may beheterocyclic(lower)alkanoyl (e.g., thienylacetyl, furylacetyl,pyrrolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, piperazinylacetyl,etc.); heterocyclicoxycarbonyl (e.g. 8-quinolyloxycarbonyl, etc.);heterocycliccarbonyl (e.g., thenoyl, furoyl, nicotinoyl, isonicotinoyl,pyrrolecarbonyl, pyrrolidinecarbonyl, tetrahydropyrancarbonyl, etc.);heterocyclic-(lower)alkoxycarbonyl (e.g. 2-pyridylmethoxycarbonyl,etc.).

Suitable substituted or unsubstituted carbamoyl may include carbamoyl,lower alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.),arylcarbamoyl (e.g., phenylcarbamoyl, etc.), ar(lower)alkylcarbamoyl(e.g., benzylcarbamoyl, tritylcarbamoyl, etc.), lower alkanoylcarbamoyl(e.g., formylcarbamoyl, acetylcarbamoyl, etc.), mono(or di ortri)halo(lower)alkanoylcarbamoyl (e.g., chloroacetylcarbamoyl,trichloroacetylcarbamoyl, etc.), and the like.

The "acyl" as stated above may optionally have 1 to 3 suitablesubstituent(s) such as halogen (e.g., chlorine, bromine, iodine orfluorine), hydroxy, cyano, nitro, lower alkoxy, lower alkyl, loweralkenyl, acyl[preferably mono(or di or tri)halo(lower)alkanoyl (e.g.,chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.)],aryl (e.g., phenyl, tolyl, etc.), or the like.

Preferable examples of said "protective group" in the terms "a protectedamino group" and "a protected amino(lower)alkyl group" are acyl, andmore preferably lower alkanoyl (e.g., formyl, acetyl, propionyl,butyryl, isobutyryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.),mono(or di or tri)halo(lower)-alkanoyl (e.g., chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc.) and loweralkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,pentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.).

Suitable "lower alkyl" may include straight or branched saturatedaliphatic hydrocarbon residue such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, andthe like, and preferably one having 1 to 4 carbon atoms.

Suitable "organic residue which may have suitable substituent(s)" mayinclude:

lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.);

mono(or di or tri)halo(lower)alkyl (e.g., chloromethyl, dichloromethyl,trichloromethyl, bromomethyl, chloroethyl, dichloroethyl,trichloroethyl, fluoroethyl, trifluoroethyl, etc.);

lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl,etc.);

lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl,1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or5-hexynyl, etc.);

aryl (e.g., phenyl, tolyl, xylyl, cumenyl, naphthyl, etc.);

ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl,phenylpropyl, etc.); and the like.

halo(lower)alkanoyl (e.g. chloroacetyl, dichloroacetyl, etc.); and thelike.

Suitable "lower alkoxy" may be straight or branched and include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy,neopentyloxy, hexyloxy and the like, and preferably one having 1 to 4carbon atoms.

Suitable "halogen" may be chlorine, bromine, iodine or fluorine.

Suitable "lower alkanoyloxylmethyl" may include acetoxymethyl,propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl,valeryloxymethyl, isovaleryloxymethyl, pivaloyloxymethyl,hexanoyloxymethyl and the like.

Suitable "lower alkanoylthiomethyl" may include acetylthiomethyl,propionylthiomethyl, butyrylthiomethyl, isobutyrylthiomethyl,valerylthiomethyl, isovalerylthiomethyl, pivaloylthiomethyl,hexanoylthiomethyl, and the like.

Suitable "heterocyclic moiety" in the terms "heterocyclicthiomethylwhich may have suitable substituent(s)" and "heterocyclic-thio which mayhave suitable substituent(s)" may be one containing at least one heteroatom selected from nitrogen, sulfur and oxygen atom, and may includesaturated or unsaturated, monocyclic or polycyclic heterocyclic group,and preferable heterocyclic group may be N-containing heterocyclic groupsuch as unsaturated 3 to 6 membered heteromonocyclic group containing 1to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, pyridazinyl,triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc.;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 4nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl, etc.); unsaturated condensed heterocyclic group containing1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.;

unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl, etc.);

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.);

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), etc.;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl, etc.);

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atomsand 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl,etc.) and the like; wherein said heterocyclic group may have 1 to 4suitable substituents selected from lower alkyl or lower cycloalkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, etc.);

lower alkenyl (e.g. vinyl, allyl, 1 or 2 or 3-propenyl, 1 or 2 or 3 or4-butenyl, 1 or 2 or 3 or 4 or 5-pentenyl, etc.); amino(lower)alkyl(e.g., aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl,4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc.); a protectedamino(lower)alkyl group such as lower alkoxycarbonylamino(lower)alkyl(e.g. tert-butoxycarbonylaminomethyl, etc.); carboxy(lower)alkyl (e.g.,carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl,4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, etc.);sulfo(lower)alkyl (e.g., sulfomethyl, 2-sulfoethyl, 2-sulfopropyl,3-sulfopropyl, 4-sulfobutyl, 5-sulfopentyl, 6-sulfohexyl, etc.); phenylwhich may have 1 to 3 halogen atom(s) (e.g. phenyl, 2 or 3 or4-chlorophenyl, 2 or 3 or 4-bromophenyl, etc.); and loweralkylamino(lower)alkyl (e.g., N-methylaminomethyl,N,N-dimethylaminomethyl, 2-(N-methylamino)ethyl,2-(N,N-dimethylamino)ethyl, 2-(N-methyl-N-ethylamino)ethyl,3-(N-methylamino)propyl, 3-(N,N-dimethylamino)propyl,3-(N,N-diethylamino)propyl, 4-(N-methylamino)butyl,4-(N,N-dimethylamino)butyl, 4 -(N-methyl-N-ethylamino)butyl,5-(N-methylamino)pentyl, 5-(N,N-dimethylamino)pentyl,6-(N,N-diethylamino)hexyl, 6-(N,N-dimethylamino)hexyl, etc.).

And preferable examples of said "heterocyclic moiety" are:

thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) which may have a substituent selected from thegroups consisting of lower alkyl(e.g., methyl, ethyl, propyl, isopropyl,butyl, pentyl, hexyl, etc.), amino(lower)alkyl (e.g., aminomethyl,aminoethyl, aminopropyl, etc.) and lower alkoxycarbonylamino(lower)alkyl(e.g., methoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl,ethoxycarbonylaminoethyl, etc.);

oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.) which may have halophenyl (e.g.,2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, etc.);

tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl,) which may havesubstituent selected from the groups consisting of lower alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.),carboxy(lower)alkyl (e.g., carboxymethyl, carboxyethyl, carboxypropyl,etc.), lower alkenyl (e.g., vinyl, allyl, etc.) and amino(lower)alkyl(e.g., aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl,4-aminobutyl, 5-aminopentyl, 6-aminohexyl, etc.);

pyrazinyl; and

tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.).

"Heterocyclic" moiety in the terms "heterocyclic-thiomethyl having aprotected amino(lower)alkyl group" and "heterocyclic-thiomethyl havingan amino(lower)alkyl group" may be the same as exemplified above, andthus defined heterocyclic moiety is preferably loweralkoxycarbonylamino(lower)alkylthiadiazolyl andamino(lower)alkylthiadiazolyl as aforementioned, respectively.

Suitable "lower alkylene" may include methylene, ethylene, trimethylene,1-methylethylene, etc., preferably one having 1 to 3 carbon atoms, morepreferably one having 1 to 2 carbon atoms and the most preferablymethylene.

Suitable "carboxy derivative" includes protected carboxy such asesterified carboxy. And suitable examples of said ester may be the onessuch as lower alkyl ester (e.g., methyl ester, ethyl ester, propylester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,pentyl ester, t-pentyl ester, hexyl ester, 1-cyclopropylethyl ester,etc.);

lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);

lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.);

lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester,isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester,etc.);

lower alkylthioalkyl ester (e.g., methylthiomethyl ester,ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester,etc.);

mono(or di or tri)-halo(lower)alkyl ester (e.g., 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.);

lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethylester,proionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester,pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, etc.);

lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester,2-mesylethyl ester etc.);

ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which mayhave one or more suitable substituent(s) (e.g., benzyl ester,4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, tritylester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);

aryl ester which may have one or more suitable substituent(s) such assubstituted or unsubstituted phenyl ester (e.g., phenyl ester, tolylester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester;

lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) andthe like.

Suitable "a protected carboxy group" may include esterified carboxy asaforementioned.

Suitable "a conventional group which is capable to be replaced by theresidue (-R⁷) of the compound of the formula: HR⁷ " in the symbol Y mayinclude halogen (e.g., chlorine, bromine, etc.), azido, acyloxy such aslower alkanoyloxy (e.g., formyloxy, acetoxy, propionyloxy, butyryloxy,etc.), and the like.

Suitable "arylthio" may include phenylthio, tolylthio, xylylthio,mesitylthio, naphthylthio and the like.

The processes for preparing the object compounds (I) of the presentinvention are explained in detail in the following.

Process 1:

The object compound (I) or a salt thereof can be prepared by reacting a7-aminocephalosporanic acid derivative (II) or its reactive derivativeat the amino group or a salt thereof with a carboxylic acid (III) or itsreactive derivative at the carboxy group or a salt thereof.

As to the starting compounds to be used in this process, the7-aminocephalosporanic acid derivatives (II) have been publicly knownand can be prepared by the method known to the art in the cephalosporinfield, and the carboxylic acid (III) can be prepared according to amanner as disclosed in Processes A to Q.

Suitable reactive derivative at the amino group of the compound (II) mayinclude a conventional reactive derivative used in amidation reaction,for example, a silyl derivative formed by the reaction of the compound(II) with a silyl compound such as bis(trimethylsilyl)acetamide,trimethylsilylacetamide, etc.; isocyanato, isothiocyanato, etc.;Schiff's base or its tautomeric enamine type isomer formed by thereaction of the amino group with a carbonyl compound such as an aldehydecompound (e.g., acetaldehyde, isopentaldehyde, benzaldehyde,salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde,m-chlorobenzaldehyde, p-chlorobenzaldehyde, hydroxynaphthoaldehyde,furfural, thiophenecarboaldehyde, etc.) or a ketone compound (e.g.,acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone,ethyl acetoacetate, etc.), and the like.

Suitable derivatives at the carboxy group of the compound (II) andsuitable salts of the compound (II) are to be referred to the onesexemplified for the compound (I).

Suitable reactive derivatives at the carboxy group of the compound (III)may include, for example, an acid halide, an acid anhydride, anactivated amide, an activated ester, and the like, and preferably anacid chloride and acid bromide; a mixed acid anhydride with an acid suchas substituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g., methylcarbonate, ethyl carbonate, propyl carbonate, etc.), aliphaticcarboxylic acid (e.g, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; anactivated acid amide with a heterocyclic compound contained iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole or tetrazole; an activated ester (e.g., cyanomethyl ester,methoxymethyl ester, dimethylaminomethyl ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidinylester,8-quinolyl thioester, or an ester with a N-hydroxy compound such asN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole,1-hydroxy-6-chlorobenzotriazole, etc.), and the like. The suitablereactive derivative can optionally be selected from the above accordingto the kind of the compound (III) to be used practically.

Suitable salts of the compound (III) may include a salt with aninorganic base such as an alkali metal salt (e.g., sodium or potassiumsalt), an alkaline earth metal salt (e.g., calcium or magnesium salt), asalt with an organic base such as trimethylamine, triethylamine, an acidaddition salt (e.g., hydrochloride), and the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, benzene, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence the reaction. Among these solvents, hydrophilicsolvents may be used in a mixture with water. The reaction can beusually carried out under cooling.

When the carboxylic acid (III) is used in a form of the free acid orsalt in this reaction, the reaction is preferably carried out in thepresence of a condensing agent such as a carbodiimide compound (e.g.,N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.), a keteniminecompound (e.g., N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g., ethoxyacetylene), β-chlorovinylethyl ether, a sulfonicacid ester of N-hydroxybenzotriazole derivative (e.g.,1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.), aphosphorus compound (e.g., trialkyl phosphite, ethyl polyphosphate,isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride,triphenylphosphine, etc.), thionyl chloride, oxalyl chloride,N-ethyl-benzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to as so-called "Vilsmeier reagent") formed by thereaction of an amide compound such as dimethylformamide,diethylacetamide, N-methylformamide or the like with a halogen compoundsuch as thionyl chloride, phosphoryl chloride, phosgene or the like.

Process 2:

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to elimination reaction of theamino-protective group.

The elimination reaction is carried out by a conventional method such ashydrolysis, reduction or the like.

These methods may be selected depending on the kind of the protectinggroup to be eliminated.

The hydrolysis may include a method being conducted in the presence ofan acid (referred to as acidic hydrolysis hereinafter), base (referredto as basic hydrolysis hereinafter), hydrazine, or the like.

Among these methods, acidic hydrolysis is one of the common andpreferable method for eliminating the protective group such assubstituted or unsubstituted alkoxycarbonyl (e.g., t-butoxycarbonyl,t-pentyloxycarbonyl, trichloroethoxycarbonyl, etc.), substituted orunsubstituted alkanoyl (e.g., formyl, etc.) lower cycloalkoxycarbonyl,substituted or unsubstituted ar(lower)alkoxycarbonyl (e.g.,benzyloxycarbonyl, substituted henzyloxycarbonyl, etc.), ar(lower)alkyl(e.g., benzyl, trityl, etc.), substituted phenylthio, substitutedaralkylidene, substituted alkylidene, substituted lower cycloalkylidene,or the like. Suitable acid for the hydrolysis includes an organic or aninorganic acid, for example, formic acid, trifluoroacetic acid,benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and thelike. Preferable acid is one which can easily be removed from thereaction mixture by a conventional manner such as distillation underreduced pressure, for example, formic acid, trifluoroacetic acid,hydrochloric acid, etc. The acid suitable for the reaction can beselected according to the kind of protective group to be eliminated, andthe elimination reaction can be carried out in the presence or absenceof a solvent. Suitable solvent includes a conventional organic solvent,water or a mixture thereof. When the hydrolysis is carried out in thepresence of trifluoroacetic acid, the reaction may be preferably carriedout in the presence of anisole.

The basic hydrolysis is preferable applied for eliminating theprotective group such as haloalkanoyl (e.g., trifluoroacetyl, etc.),etc. Suitable base includes, for example, an inorganic base such asalkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide,etc.), alkaline earth metal hydroxide (e.g., magnesium hydroxide,calcium hydroxide, etc.), alkali metal carbonate (e.g., sodiumcarbonate, potassium carbonate, etc.), alkaline earth metal carbonate(e.g., magnesium carbonate, calcium carbonate, etc.), alkali metalbicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.),alkaline earth metal phosphate (e.g., magnesium phosphate, calciumphosphate, etc.), alkali metal hydrogen phosphate (e.g., disodiumhydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like,and an organic base such as alkali metal acetate (e.g., sodium acetate,potassium acetate, etc.), alkali metal alkoxide (e.g., sodium methoxide,sodium ethoxide, sodium propoxide, etc.), trialkylamine (e.g.,trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4,3,0]-5-nonene,1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]-5-undecene or thelike. The basic hydrolysis is often carried out in water or ahydrophilic or moistened organic solvent or a mixture thereof.

The hydrolysis using hydrazine is commonly applied for eliminating theprotective group such as succinyl or phthaloyl.

The protecting group can generally be eliminated by hydrolysis asmentioned above or by the other conventional hydrolysis. In case thatthe protective group is halo(lower)alkoxycarbonyl or8-quinolyloxycarbonyl, they are eliminated preferably by treating with aheavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating theprotective group such as halo(lower)alkoxycarbonyl (e.g.,trichloroethoxycarbonyl etc.), substituted or unsubstitutedaralkoxycarbonyl (e.g., benzyloxycarbonyl, substituted benzyloxycarbonyletc.), 2-pyridylmethoxycarbonyl, benzyl, etc. Suitable reduction mayinclude, for example, reduction with an alkali metal borohydride (e.g.,sodium borohydride, etc.) and the like.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group to be eliminated andthe method to be applied, and the present reaction is preferably carriedout under a mild condition such as under cooling, at ambient temperatureor slightly elevated temperature.

Process 3:

The object compound (Id) or a salt thereof can be prepared by subjectingthe compound (Ic) or a salt thereof to elimination reaction of theaminoprotective group in R_(a) ⁴.

The present reaction is carried out by conventional method, such ashydrolysis, reduction or the like. The method of hydrolysis andreduction and the reaction conditions (e.g. reaction temperature,solvent, etc.) are substantially the same as those illustrated for theelimination of the protective group of the protected amino group forR_(a) ^(1') of the compound (Ia) in the above Process 2 and thereforeare to be referred to said explanation.

Process 4:

The object compound (If) can be prepared by subjecting the compound (Ie)to elimination reaction of a carboxy-protective group.

The present reaction is carried out by conventional method, such ashydrolysis, reduction or the like. The methods of hydrolysis andreduction and the reaction conditions (e.g., reaction temperature,solvent, etc.) are substantially the same as those illustrated for theelimination of the protective group of the protected amino group forR_(a) ^(1') of the compound (Ia) in the Process 2 and therefore are tobe referred to said explanation.

Process 5:

The object compound (Ih) or a salt thereof can be prepared by reactingthe compound (Ig) or a salt thereof with the compound (IV) or itsreactive derivative at the mercapto group.

Suitable reactive derivative at the mercapto group of the compound (IV)may include a metal salt such as an alkali metal salt (e.g., sodiumsalt, potassium salt, etc.) an alkaline earth metal salt (e.g.,magnesium salt, etc.) and the like.

The reaction may be preferably carried out in a solvent such as water,acetone, chloroform, nitrobenzene, N,N-dimethylformamide, methanol,ethanol, dimethylsulfoxide, or any other organic solvents, which do notadversely influence the reaction and an optional mixture thereof,preferably in a rather high polar solvents. The reaction is preferablycarried out in around neutral condition. When the compound (Ig) or thecompound (IV) is used in a free form, the reaction is preferablyconducted in the presence of a base such as alkali metal hydroxide,alkali metal carbonate, alkali metal bicarbonate, trialkylamine or thelike. The reaction is usually carried out at ambient temperature orslightly elevated temperature.

The present invention may include, within its scope, the cases that theprotected amino group and/or the derivative at the carboxy group aretransformed into the corresponding free amino group and/or carboxy groupduring the reaction or post-treatment in the processes as explainedabove.

The object compounds (I) obtained according to the processes 1-5 asexplained above can be used without any isolation in the subsequentprocesses.

Processes A to Q for preparing the starting compounds are explained indetail as follows.

Process A:

The compound (A-3) or a salt thereof can be prepared by reacting thecompound (A-1) or a salt thereof with the compound (A-2).

The present reaction is usually carried out in the presence of a base asaforementioned in Process 2 in a conventional solvent which does notadversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling or at ambient temperature.

Process B:

The compound (B-2) or a salt thereof can be prepared by reacting thecompound (A-1) or a salt thereof with the compound (B-1) or a saltthereof.

The present reaction is substantially the same as Process A, andaccordingly the reaction conditions (e.g. a base, reaction temperature,solvent, etc.) can be referred to those of Process A.

Process C:

The compound (C-2) or a salt thereof can be prepared by reacting thecompound (C-1) or a salt thereof with carbon dioxide.

The present reaction is usually carried out in the presence of a basesuch as alkyl lithium (e.g. butyl lithium, etc.) or the like in aconventional solvent which does not adversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling or at ambient temperature.

Process D:

The compound (D-2) or a salt thereof can be prepared by reacting thecompound (D-1) or a salt thereof with an halogenating agent.

Suitable halogenating agent may include a conventional one used forhalogenation of hydroxy group such as phosphorus compound (e.g.,phosphoryl chloride, phosphorus trichloride, phosphorus tribromide,phosphorus pentachloride, etc.) or the like.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under warming to heating.

Process E:

The compound (E-2) can be prepared by subjecting a compound (E-1) todehalogenative reduction. The dehalogenative reduction to be used inthis process is a conventional one such as a catalytic reduction (e.g.,palladium on carbon, palladium black, spongy palladium, etc.) and thelike.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout at ambient temperature.

Process F:

The compound (F-2) or a salt thereof can be prepared by reacting thecompound (F-1) or a salt thereof with a nucleophile selected fromalkanol and arenethiol or a salt thereof.

The present reaction is usually carried out in the presence of a base asaforementioned in Process 2 in a conventional solvent which does notadversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling or at ambient temperature.

Process G:

The compound (G-2) or a salt thereof can be prepared by reacting thecompound (G-1) or a salt thereof with a carboxy protective agent.

Suitable agent to be used in this reaction may include conventional onessuch as lower alkyl halide (e.g. methyl iodide, etc.)di(lower)alkylsulfate (e.g. dimethylsulfate, etc.), diazo(lower)alkane(e.g. diazomethane, etc.), lower alkanol (e.g. methanol, ethanol, etc.)or the like.

The present reaction is usually carried out in the presence of an acidas aforementioned in Process 2 in a conventional solvent which does notadversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling to heating.

Process H:

The compound (H-2) can be prepared by reacting the compound (H-1) with acompound of the formula: R¹⁰ SCH₂ SOR¹⁰.

The present reaction is usually carried out in the presence of a base asaforementioned Process 2 in a conventional solvent which does notadversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout under cooling to under heating.

Process I:

The compound (I-1) can be prepared by reacting the compound (H-2) withan acid and/or acid anhydride such as acetic acid and/or aceticanhydride. The reaction can preferably be carried out in the presence ofalkali metal perchlorate (e.g. sodium perchlorate, potassiumperchlorate, etc.), alkaline earth metal perchlorate (e.g., magnesiumperchlorate, calcium perchlorate, etc.) and the like, and an acid suchas an organic carboxylic acid (e.g., formic acid, etc.).

The reaction temperature is not critical and the reaction is preferablycarried out under warming to heating.

Process J:

The compound (J-2) or a salt thereof can be prepared by subjecting thecompound (J-1) to elimination reaction of the carboxy-protective group.

The present reaction can be carried out in substantially the same manneras that of Process 4. Accordingly, the detailed explanation therefor isto be referred to said Process 4.

Process K

The compound (K-2) or a salt thereof can be prepared by reacting thecompound (K-1) or a salt thereof with an amino-protective agent. Whenthe amino-protective agent is acylating agent, the reaction can becarried out in substantially the same manner as that of Process 1.Accordingly, the detailed explanation therefor is to be referred to saidProcess 1.

Process L:

The compound (L-2) can be prepared by oxidizing the compound (L-1).

The present oxidation reaction is conducted by a conventional methodwhich is applied for the transformation of so-called activated methylenegroup into carbonyl group. That is, the present oxidation is conductedby a conventional method such as oxidation by using selenium dioxide orthe like.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferablycarried out under warming to heating.

Process M:

The compound (M-2) or a salt thereof can be prepared by reacting thecompound (M-1) or its hydrate or a salt thereof with a compound of theformula: R⁶ --ONH₂ or a salt thereof.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction, and when a salt of thecompound of the formula: R⁶ --ONH₂ is used in the reaction, the reactionis preferably carried out in a presence of a base as aforementioned inProcess 2.

The reaction temperature is not critical and the reaction can be carriedout at ambient temperature.

Process N:

The compound (N-2) or a salt thereof can be prepared by subjecting thecompound (N-1) or a salt thereof to elimination reaction of theamino-protective group.

The present reaction can be carried out in substantially the same manneras that of Process 2. Accordingly, the detailed explanation therefor isto be referred to said Process 2.

Process O:

The compound (O-2) or a salt thereof can be prepared by reacting thecompound (O-1) or a salt thereof with a nitrosating agent.

Suitable nitrosating agent may include a conventional one such as alkalimetal nitrite (e.g., sodium nitrite, potassium nitrite, etc.) and thelike.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction is preferablycarried out under cooling or at ambient temperature.

Process P:

The compound (P-2) or a salt thereof can be prepared by reacting thecompound (P-1) or a salt thereof with a substituting agent capable forsubstituting a hydrogen atom of the hydroxy in the compound (P-1) byR^(6') group.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

When the substituting agent is diazo compound, the reaction can becarried out under cooling or at ambient temperature.

Process Q:

The compound (Q-2) or a salt there of can be prepared by reacting thecompound (Q-1) or a salt thereof with a halogenating agent.

Suitable halogenating agent may include a conventional one used forhalogenation of an aromatic ring such as chlorine, bromine and the like.

The present reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction.

The reaction temperature is not critical and the reaction can be carriedout at ambient temperature.

It is to be noted that, in the aforementioned reactions and/or thepost-treatment of the reaction mixture, the aforementioned geometricisomer may be occasionally transformed into the other geometric isomerand such case is also included in the scope of the present invention.

In case that the object compound (I) have a free carboxy group at 4position and/or a free amino group for R_(a) ¹, it may be transformedinto its pharmaceutically acceptable salt by a conventional method.

All of the object compounds (I) and nontoxic pharmaceutically acceptablesalt thereof of the present invention are novel and exhibit highantibacterial activity, inhibiting the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativebacteria and are useful as antibacterial agents. Now, in order to showthe utility of the object compounds (I), the test data on the in vitroantibacterial activity of some representative compounds (I) of thisinvention are shown in the following.

IN VITRO ANTIBACTERIAL ACTIVITY Test Method

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (approximately 10⁶ variable cells per ml.) wasstreaked on heart infusion agar (III-agar) containing gradedconcentrations of antibiotics, and the minimal inhibitory concentration(MIC) was expressed in terminal of μg/ml after incubation at 37° C. for20 hours.

Test Compounds

No. 1:7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 2:7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

No. 3:7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 4:7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 5:7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

No. 6:7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

No. 7:7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid.

No. 8:7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

No. 9:7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid(syn isomer).

No. 10:7-[2-(2-aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid.

No. 11:7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 12:7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 13:7-[2-(6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

No. 14:7-[2-(6-aminopyridin-2-yl)-2-ethoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

    ______________________________________                                        Test Results                                                                  MIC (μg/ml.)                                                                          Microorganisms                                                                                Pseuodomonas                                                    Proteus       aeruginosa                                         Compound No. vulgaris IAM 1025                                                                           NCTC-10490                                         ______________________________________                                        1            <0.025        <1.56                                              2            <0.025        6.25                                               3            0.05          <1.56                                              4            <0.025        <1.56                                              5            0.025         <1.56                                              6            ≦0.025 ≦1.56                                       7            ≦0.025 6.25                                               8            0.05          3.13                                               9            ≦0.025 ≦1.56                                       10           0.2           6.25                                               11           ≦0.025 <1.56                                              12           0.05          ≦1.56                                       13           0.05          ≦1.56                                       14           0.05          <1.56                                              ______________________________________                                    

For therapeutic administration, the object compounds (I) andpharmaceutically acceptable salt thereof of the present invention areused in the form of conventional pharmaceutical preparation whichcontains said compound, as an active ingredient, in admixture withpharmaceutically acceptable carriers such as an organic or inorganicsolid or liquid excipient which is suitable for oral, parenteral orexternal administration. The pharmaceutical preparations may be in solidform such as capsule, tablet, dragee, ointment or suppository, or inliquid form such as solution, suspension, or emulsion. If needed, theremay be included in the above preparations auxiliary substances,stabilizing agents, wetting or emulsifying agents, buffers and the othercommonly used additives.

While the dosage of the compounds may vary from and also depend upon theage, conditions of the patient, a kind of disease, a kind of thecompounds (I) to be applied, etc. In general, amounts between 1 mg. andabout 2000 mg. or even more per day may be administered to a patient. Anaverage single dose of about 50 mg., 100 mg., 250 mg., and 500 mg. ofthe object compounds (I) of the present invention may be used intreating diseases infected by pathogenic bacteria.

The following examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1

(1) Phosphoryl chloride (0.998 g.) was added to N,N-dimethylformamide (5ml.) and stirred at 40° C. for 30 minutes. To the solution was added asolution of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (synisomer) (1.125 g.) in N,N-dimethylformamide (5 ml.) at -15° C., andstirred at -10° to -8° C. for 50 minutes [solution A]. On the otherhand,7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (2.007 g.) and trimethylsilylacetamide (7.22 g.) were dissolved inmethylene chloride (20 ml.) at 40° C. and cooled. To the cool solutionwas added the above solution A at -20° to -15° C. and stirred at thesame temperature for 40 minutes. The resultant solution was poured intoa solution of a saturated aqueous solution of sodium bicarbonate (30ml.) and water (40 ml.) under ice cooling. The aqueous layer wasseparated, washed with ethyl acetate, and then ethyl acetate (50 ml.)was added to the aqueous layer. The solution was adjusted to pH 3 with10% hydrochloric acid, and extracted with ethyl acetate twice. Theextract was washed with water and concentrated to a small amount underreduced pressure. The appeared precipitates were collected byfiltration, washed with ethyl acetate and dried to give7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (873 mg.). The same product (126 mg.) was recoveredfrom the mother liquor. Total yield was 999 mg.

I.R. ν_(max) ^(Nujol) : 3280, 1785, 1728, 1673, 1454, 1053 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.62, 3.76 (2H, Ab-q, J=18 Hz), 3.90 (3H, s),3.94 (3H, s), 4.24, 4.35 (2H, AB-q, J=16 Hz), 5.16 (1H, d, J=5 Hz), 5.85(1H, dd, J=5 Hz, 8 Hz), 7.50 (1H, d, J=8 Hz), 7.80 (1H, t, J=8 Hz), 8.00(0.3H, broad s), 6.88 (0.7H, broad d, J=8 Hz), 9.28 (0.7H, broad d, J=10Hz), 8.28 (0.3H, broad s), 9.50 (1H, broad d, J=8 Hz), 10.7 (1H, m, J=10Hz).

(2) A mixture of N,N-dimethylformamide (3 ml.) and phosphoryl chloride(460 mg.) was stirred at 37° to 40° C. for 30 minutes. To the solutionwere added methylene chloride (3 ml.) and2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (669 mg.) at -20°to -25° C. and stirred at -10° to -15° C. for one hour. A solution of4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (670 mg.) andtrimethylsilylacetamide (2 g.) in methylene chloride (200 ml.) was addedto the above solution at -10° to -15° C., and then stirred at the sametemperature for 30 minutes. After the solution was concentrated underreduced pressure, ethyl acetate and water were added to the residue. Theethyl acetate layer was separated, washed with an aqueous solution ofsodium bicarbonate, water and a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate and then concentrated underreduced pressure. The residue was triturated with diethyl ether to give4-nitrobenzyl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate(730 mg.), mp. 195° to 200° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1790, 1725, 1690, 1660 cm⁻¹.

The following compounds were prepared in substantially the same manneras those of Example 1-(1) and (2).

(3)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 167° to 169° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3270, 1780, 1670, 1455, 1370, 1252, 1052 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.65, 3.78 (2H, AB-q, J=18 Hz), 3.97 (3H, s),4.30, 4.57 (2H, AB-q, J=12 Hz), 5.22 (1H, d, J=5 Hz), 5.93 (1H, dd, J=5Hz, 8 Hz), 6.57 (1H, broad d, J=7 Hz), 7.58 (1H, d, J=7 Hz), 7.90 (1H,t, J=7 Hz), 9.3-9.8 (2H, m), 9.63 (1H, s), 10.62, 10.70 (1H, m).

(4)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 178° to 186° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3280, 1785, 1720-1660 (broad), 1457, 1255, 1162,1052 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.40 (9H, s), 3.63, 3.78 (2H, AB-q, J=18 Hz),3.98 (3H, s), 4.1-4.7 (4H, m), 5.21 (1H, d, J=4.5 Hz); 5.89 (1H, dd,J=4.5 Hz, 8 Hz), 6.2-8.2 (4H, m), 8.33 (0.3H, broad s), 9.35 (0.7H,broad d, J=10 Hz), 9.55 (1H, broad d, J=8 Hz), 10.5-10.8 (1H, m).

(5)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer), mp. 191° to 193° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1725, 1665, 1240, 1053 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 2.03 (3H, s), 3.53, 3.62 (2H, AB-q, J=17 Hz),3.97 (3H, s), 4.70, 5.02 (2H, AB-q, J=13 Hz), 5.18 (1H, d, J=5 Hz), 5.88(1H, dd, J=5 Hz, 8 Hz), 6.90 (1H, broad d, J=7 Hz), 7.53 (1H, d, J=7Hz), 7.82 (1H, t, J=7 Hz), 9.3 (1H, broad d, J=9 Hz), 9.54 (1H, d, J=8Hz), 10.6 (1H, m).

(6) 4-Nitrobenzyl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate(syn isomer), mp. 162° to 168° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1735, 1690-1660, 1040 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.70, 4.10 (2H, AB-q, J=18 Hz), 3.93 (3H, s),5.32 (1H, d, J=5 Hz), 5.45 (2H, s), 5.98 (1H, dd, J=5 Hz, 8 Hz), 6.9(1H, m), 7.50 (1H, d, J=8 Hz), 7.57 (2H, d, J=8 Hz), 7.83 (1H, m), 8.26(2H, d, J=8 Hz), 9.30 (1H, m), 9.69 (1H, d, J=8 Hz), 10.70 (1H, m).

(7) 4-Nitrobenzyl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylate.

I.R. ν_(max) ^(Nujol) : 3700-3000, 1780, 1710-1640, 1050, 1010, 640cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3:7 (2H, broad s), 3.84 (3H, s), 3.99 (3H, s),5.25 (1H, d, J=5 Hz), 5.36 (2H, s), 5.77 (1H, dd, J=5 Hz, 8 Hz), 6.9(1H, m), 7.52 (1H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz), 7.8 (1H, m), 8.22(2H, d, J=8 Hz), 9.3 (1H, m), 9.52 (1H, d, J=8 Hz), 10.7 (1H, m).

(8) Benzhydryl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3230, 1780, 1725, 1680 cm⁻¹.

N.M.R. δ ppm (acetone-d₆): 3.59 (3H, s), 3.63, 3.73 (2H, AB-q, J=18 Hz),3.83 (3H, s), 3.96 (3H, s), 4.23, 4.43 (2H, AB-q, J=13 Hz), 5.10 (1H,s), 6.86 (1H, s), 7.16-7.80 (13H, m).

(9)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 198° to 202° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380-3070, 1790, 1735, 1670 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.47 (3H, d, J=7 Hz), 3.5-4.2 (1H, m), 4.00 (3H,s), 5.20 (1H, d, J=5 Hz), 6.05 (1H, dd, J=5 Hz, 8 Hz),, 6.67 (1H, d, J=6Hz), 6.9-8.7 (3H, m).

(10)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 225° to 225.5° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 3220, 1773, 1730, 1680-1650, 1560,1260, 1160, 1050 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 2.02 (3H, s), 3.3, 3.6 (2H, AB-q, J=18 Hz), 3.96(3H, s), 5.13 (1H, d, J=4.5 Hz), 5.78 (1H, dd, J=4.5 Hz, 8 Hz), 6.9-8.3(3H, m), 9.3-9.5 (2H, m), 10.55 (1H, m).

(11)7-[2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer), mp. 151° to 155° C.

I.R. ν_(max) ^(Nujol) : ˜3260, 1775, 1730, 1690-1670, 1380, 1160, 1040cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 2.00 (3H, s), 3.5 (2H, broad s), 3.98 (3H, s),4.67, 5.03 (2H, AB-q, J=12 Hz), 5.18 (1H, d, J=5 Hz), 5.88 (1H, dd, J=5Hz, 8 Hz), 7.5-8.0 (3H, m), 9.51 (1H, d, J=8 Hz), 11.63 (1H, m).

(12)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185° to 190° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1790, 1700, 1665 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.60, 3.42 (2H, AB-q,, J=18 Hz), 3.98 (3H, s),4.64, 4.92 (2H, AB-q, J=12 Hz), 5.20 (1H, d, J=4 Hz), 5.90 (1H, dd, J=4Hz, 9 Hz), 6.50 (2H, s), 6.8-8.0 (3H, s), 9.58 (1H, d, J=9 Hz).

(13)7-[2-(2-Formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid, mp. 138° to 155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1787, 1565, 1408, 1043 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.63, 3.76 (2H, AB-q, J=18 Hz), 3.92 (3H, s),4.02 (3H, s), 4.24, 4.35 (2H, AB-q, J=12 Hz), 5.16 (1H, d, J=5 Hz), 5.86(1H, dd, J=5 Hz, 9 Hz), 7.47 (1H, d, J=6 Hz), 8.63 (1H, d, J=6 Hz), 9.37(1H, d, J=10 Hz), 9.60 (1H, d, J=9 Hz), 11.00 (1H, d, J=10 Hz).

(14)7-[2-(6-Formamidopyridin-2-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1700, 1660 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.30 (3H, t, J=7 Hz), 3.65, 3.80 (2H, AB-q, J=16Hz), 3.95 (3H, s), 4.25 (2H, q, J=7 Hz), 4.28 (2H, broad s), 5.18 (1H,d, J=5 Hz), 5.90 (1H, dd, J=5 Hz, 9 Hz), 6.8-8.2 (3H, m), 9.4 (2H, m),10.6 (1H, broad d).

(15) A solution of pivaloyl chloride (1.07 g.) in methylene chloride (3ml.) was added to a solution of 2-(6-Formamidopyridin-2-yl)acetic acid(1.6 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) in methylenechloride (25 ml.) at -20° to -25° C., and stirred at the sametemperature for one hour [solution A]. On the other hand, a solution of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (3.24 g.) and 1,5-diazabicyclo[5,4,0]undecene-5 (1.35 g.) inmethylene chloride (60 ml.) was stirred at room temperature for 10minutes. To the solution was added the above solution A at -20° to -25°C. and stirred at the same temperature for 1.5 hours. After removing thesolvent from the resultant solution, ethyl acetate, water and sodiumbicarbonate were added to the residue. The aqueous layer was separatedand washed with ethyl acetate. Ethyl acetate (300 ml.) was added to theaqueous solution, adjusted to pH 2 to 3 with 5% hydrochloric acid, andthen shaken sufficiently. The ethyl acetate layer was separated, washedwith water and concentrated under reduced pressure to give7-[2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (2.2 g.).

I.R. ν_(max) ^(Nujol) : 3320, 1782, 1690 (broad) cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.68 (4H, broad s), 3.93 (3H, s), 4.33 (2H,broad s), 5.10 (1H, d, J=5 Hz), 5.72 (1H, dd, J=5 Hz, 9 Hz), 6.8, 7.8(1H), 7.10 (1H, d, J=8 Hz), 7.73 (1H, t, J=8 Hz), 9.10 (1H, d, J=9 Hz),8.33, 9.37 (1H, broad s), 10.55 (1H, broad d, J=7 Hz).

(16) A solution of phosphoryl chloride (2.14 g.) inN,N-dimethylformamide (14 ml.) was stirred at 37° to 40° C. for 30minutes. To the solution were added methylene chloride (14 ml.) and2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (synisomer) (4.48 g.) at -20° to -25° C. and stirred at -10° to -15° C. for30 minutes [solution A]. On the other hand,7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (4.6 g.) was dissolved in a solution of trimethylsilylacetamide (14g.) in methylene chloride (150 ml.) at 40° C., and cooled to -10° to-15° C. The solution was added to the above solution A at -10° to -15°C. and stirred at the same temperature for 30 minutes. After removingmethylene chloride from the resultant solution under reduced pressure,ice water and ethyl acetate were added to the residue, and adjusted topH 4 with an aqueous solution of sodium bicarbonate. The aqueous layerwas separated, washed with ethyl acetate, adjusted to pH 2 with 10%hydrochloric acid, and then extracted with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium chloride, driedover magnesium sulfate and concentrated under reduced pressure. Theresidue was triturated with diethyl ether. The precipitates werecollected by filtration; washed with diethyl ether and dired to give7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (5.0 g.), mp. 110° to 115° C.

I.R. ν_(max) ^(Nujol) : 3240, 1780, 1700, 1660 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.73 (2H, broad s), 4.00 (3H, s), 4.35 (2H,broad s), 5.20 (1H, d, J=4 Hz), 5.93 (1H, dd, J=9 Hz, 4 Hz), 6.83-8.0(3H, m), 9.45 (1H, d, J=9 Hz). PG,52

EXAMPLE 2

(1) Conc. hydrochloric acid (127.4 mg.) was dropwise added to asuspension of7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer, 930 mg.) in methanol (15 ml.) and stirred at roomtemperature for 40 minutes. After methanol was removed under reducedpressure from the resultant solution, water (100 ml.) was added to theresidue and the solid substance was dissolved by adding 10% hydrochloricacid. After the insoluble material was filtered out, the filtrate wasadjusted to pH 3 with an aqueous sodium bicarbonate. The solution waspurified by column chromatography on macroporous, non-ionic adsorptionresin "Diaion HP-20" (Trademark, manufactured by Mitsubishi ChemicalIndustries Ltd.), with an eluent of aqueous methanol. The eluate waslyophilized to give7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (605 mg.), mp. 150° to 154° C.

I.R. ν_(max) ^(Nujol) : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.73 (2H, broad s), 3.75 (3H, s), 3.78 (3H, s),4.30 and 4.37 (2H, AB-q, J=12 Hz), 5.17 (1H, d, J=5 Hz), 5.85 (1H, dd,J=5 Hz, 9 Hz), 6.53 (1H, d, J=8 Hz), 6.93 (1H, d, J=8 Hz), 7.48 (1H, t,J=8 Hz), 9.52 (1H, d, J=9 Hz).

(2) A solution of7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (2.3 g.) in methanolic hydrochloric acid (12 ml., containinghydrochloric acid 6 mmol) was stirred at room temperature for one hour.To the resultant solution was added diethyl ether, and the precipitateswere collected by filtration and dissolved in a mixture of methanol (50ml.) and water (10 ml.). The solution was adjusted to pH 3 with anaqueous solution of sodium bicarbonate, treated with activated charcoal(1 g.) and concentrated to a volume of about 20 ml. The precipitatingcrystals were collected by filtration, washed with water and dried togive7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (1.12 g.), mp. 215° to 220° C. (dec.). The mother liquor andwashings were combined and concentrated under reduced pressure. Theappeared precipitates were collected by filtration, washed with waterand dried to give the same object compound (0.36 g.). Total yield 1.48g.

I.R. ν_(max) ^(Nujol) : 3300, 1785, l730, l670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.64 (2H, broad s), 4.06 (3H, s), 5.18 (1H, dd,J=4 Hz, 8 Hz), 5.85 (1H, dd, J=4 Hz, 8 Hz), 6.52 (1H, broad t), 6.78(1H, d, J=8 Hz), 7.19 (1H, d, J=9 Hz), 7.92 (1H, dd, J=8 Hz, 9 Hz), 10.0(1H, d, J=8 Hz).

The following compounds were prepared in substantially the same manneras those of Examples 2-(1) and (2).

(3)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 152° to 156° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.67, 3.73 (2H, AB-q, J=18 Hz), 3.83 (3H, s),4.30, 4.55 (2H, AB-q, J=14 Hz), 5.13 (1H, d, J=4 Hz), 5.82 (1H, dd, J=4Hz, 8 Hz), 6.50 (1H, dd, J=8 Hz), 6.88 (1H, d, J=8 Hz), 7.45 (1H, t, J=8Hz), 9.50 (1H, d, J=8 Hz), 9.57 (1H, s).

(4)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 169° to 177° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1670, 1620, 1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.67, 3.80 (2H, AB-q, J=14 Hz), 3.98 (3H,s), 4.27, 4.50 (2H, AB-q, J=14 Hz), 5.18 (1H, d, J=5 Hz), 5.33 (2H, s),5.88 (1H, d, J=5 Hz), 6.65 (1H, d, J=8 Hz), 6.97 (1H, d, J=8 Hz), 7.60(1H, t, J=8 Hz).

(5)7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 188° to 193° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3600-3080, 1763, 1698, 1663 cm⁻¹.

N.M.R. δppm (D₂ O+DCl): 3.83 (2H, s), 4.03 (2H, s), 4.15 (3H, s), 4.20,4.43 (2H, AB-q, J=14 Hz), 5.27 (1H, d, J=5 Hz), 5.73 (1H, d, J=5 Hz),6.93 (1H, d, J=8 Hz), 7.07 (1H, d, J=9 Hz), 7.98 (1H, dd, J=8 Hz, 9 Hz).

(6)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid hydrochloride (syn isomer), yellow powder, mp. 170° to 220° C.(dec.).

I.R. ν_(max) ^(Nujol) : 3300-3100, 1780, 1710, 1660, 1610, 1540, 1370cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.57 4.13 (2H, AB-q, J=18 Hz), 4.13 (3H, s), 5.37(1H, d, J=4.5 Hz), 5.88 (1H, dd, J=4.5 Hz, 8 Hz), 6.77 (1H, d, J=8 Hz),7.21 (1H, d, J=9 Hz), 7.97 (1H, dd, J=8 Hz, 9 Hz), 8.0-9.3 (2H, m),10.07 (1H, d, J=8 Hz).

(7)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylicacid, mp. 175° to 182° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1775, 1700-1650, 1045 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.62 (2H, broad s), 3.75 (3H, s), 3.96 (3H, s),5.15 (1H, d, J=4.5 Hz), 5.60 (1H, dd, J=4.5 Hz, 8 Hz), 6.70 (1H, d, J=8Hz), 6.85 (1H, d, J=8 Hz), 7.56 (1H, t, J=8 Hz), 9.53 (1H, d, J=8 Hz).

(8)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1700, 1680 cm⁻¹.

N.M.R. δppm (D₂ O+NaHCO₃): 3.72, 3.58 (2H, AB-q, J=17 Hz), 3.64 (3H, s),3.98 (3H, s), 4.04 (3H, s), 4.24, 4.06 (2H, AB-q, J=13 Hz), 5.20 (1H,s), 6.74 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.56 (1H, t, J=8 Hz).

(9)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 199° to 205° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258,1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.48 (3H, d, J=9 Hz), 3.7-4.2 (1H, m), 4.10 (3H,s), 5.20 (1H, d, J=5 Hz), 5.92 (1H, dd, J=9 Hz, 5 Hz), 6.62 (1H, d, J=6Hz), 6.78 (1H, d, J=8 Hz), 7.27 (1H, d, J=9 Hz), 8.00 (1H, dd, J=8 Hz, 9Hz), 10.00 (1H, d, J=9 Hz).

(10)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer), mp. 195° to 198° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3100, 1780, 1682, 1668, 1260, 1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.07 (3H, s), 3.35, 3.70 (2H, AB-q, J=18 Hz),4.11 (3H, s), 5.18 (1H, d, J=4.5 Hz), 5.77 (1H, dd, J=4.5 Hz, 8 Hz),6.80 (1H, d, J=8 Hz), 7.20 (1H, d, J=9 Hz), 7.98 (1H, dd, J=8 Hz, 9 Hz),9.95 (1H, d, J=8 Hz), 6-9.3 (2H, m).

(11)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1760, 1680 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.68 (2H, broad s), 3.93 (3H, s), 4.30 (2H, broads), 5.13 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 Hz, 9 Hz), 6.48 (1H, d, J=8Hz), 6.93 (1H, d, J=8 Hz), 7.43 (1H, t, J=8 Hz), 9.37 (1H, d, J=9 Hz).

(12)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190° to 195° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1720, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.60, 3.44 (2H, AB-q, J=17 Hz), 3.88 (3H, s),4.62, 4.88 (2H, AB-q, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4Hz, 9 Hz), 6.48 (1H, d, J=8 Hz), 6.88 (1H, d, J=8 Hz), 7.42 (1H, t, J=8Hz), 9.44 (1H, d, J=9 Hz).

(13)7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid, mp. 181° to 182.5° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.68 (2H, broad s), 3.90 (3H, s), 3.93 (3H, s),4.25, 4.33 (2H, AB-q, J=14 Hz), 5.12 (1H, d, J=5 Hz), 5.82 (1H, dd, J=5Hz, 8 Hz), 6.85 (1H, d, J=5 Hz), 8.27 (1H, d, J=5 Hz), 9.50 (1H, d, J=8Hz).

(14)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165° to 170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.28 (3H, t, J=7 Hz), 3.64, 3.76 (2H, AB-q, J=18Hz), 3.95 (3H, s), 4.18 (2H, q, J=7 Hz), 4.24, 4.38 (2H, AB-q, J=14 Hz),5.15 (1H, d, J=5 Hz), 5.84 (1H, dd, J=5 Hz, 8 Hz), 6.50 (1H, d, J=8 Hz),6.90 (1H, d, J=8 Hz), 7.43 (1H, t, J=8 Hz), 9.46 (1H, d, J=8 Hz).

(15)7-[2-(6-Trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer) (380 mg.) was added to a solution of sodium acetate(857 mg.) in water (6 ml.), and stirred at room temperature for 16hours. The resultant solution was washed with ethyl acetate (5 ml.),adjusted to pH 4 with 10% hydrochloric acid and washed with ethylacetate. The solution was concentrated under reduced pressure to 2/3 ofthe initial volume, and subjected to column chromatography onmacroporous, non-ionic adsorption resin "Diaion HP-20" (Trademark:manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 10%isopropyl alcohol. The eluate was lyophilized to give7-[2-(6-aminopyridin-2-yl)2-methoxyiminoacetamido]cephalosporanic acid(syn isomer) (130 mg.), pale yellow powder, mp. 155° to 161° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.00 (2H, s), 3.5 (2H, broad s), 3.88 (3H, s),4.67, 5.04 (2H, AB-q, J=12 Hz), 5.15 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5Hz, 8 Hz), 6.45 (1H, d, J=8 Hz), 6.88 (1H, d, J=8 Hz), 7.43 (1H, t, J=8Hz), 9.4 (1H, d, J=8 Hz).

EXAMPLE 3

A solution of7-[2-(6-formamidopyridin-2-yl)2-methoxyiminoacetamido]-3-(5-t-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.12 g.) in 98% formic acid (11 ml.) was stirred atroom temperature for 2 hours. Methanol (20 ml.) and conc. hydrochloricacid (0.3 ml.) were added to the resultant solution and then stirred atroom temperature for 30 minutes. After the reaction mixture wasconcentrated in vacuo, water (25 ml.) was added to the residue, and thenthe solution was adjusted to pH 3 to 4 with a saturated aqueous solutionof sodium bicarbonate. The solution was subjected to columnchromatography on macroporous, nonionic adsorption resin "Diaion HP-20"(Trademark, manufactured by Mitsubishi Chemical Industries Ltd.) with aneluent of aqueous methanol. The eluate was concentrated under reducedpressure and lyophilized to give7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.48 g.), mp. 248° to 251° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.53 (2H, broad s), 3.88 (3H, s), 4.35 (4H, broads), 5.05 (1H, d, J=5 Hz), 5.75 (1H, dd, J=5 Hz, 8 Hz), 6.48 (1H, d, J=8Hz), 6.88 (1H, d, J=8 Hz), 7.43 (1H, t, J=8 Hz).

EXAMPLE 4

(1) 10% Palladium on carbon (216 mg.) was added to a solution of4-nitrobenzyl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate(540 mg.) in tetrahydrofuran (10 ml.), methanol (5 ml.), acetic acid(0.075 ml.), and water (0.75 ml.). The mixture was subjected tocatalytic reduction at ambient temperature under ordinary pressure for 5hours, and then allowed to stand overnight. After filtered off thecatalyst, the filtrate was concentrated under reduced pressure. Ethylacetate and an aqueous solution of sodium bicarbonate were added to theresidue, and the aqueous layer was separated. The solution was adjustedto pH 2 with 10% hydrochloric acid. The appeared precipitates werecollected by filtration, washed with water and dried to give7-[2-(6-formamidopyridin-2-yl)2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (300 mg.), mp. 202° to 204° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 3200, 1780, 1720, 1660 cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.56 (2H, broad d), 3.96 (3H, s), 5.13 (1H,d, J=5 Hz), 5.91 (1H, d, J=5 Hz), 6.46 (1H, m), 6.85-8.00 (3H, m).

(2) A mixture of 4-nitrobenzyl7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate(syn isomer) (1.43 g.), 10% palladium on carbon (0.8 g.), methanol (30ml.) and tetrahydrofuran (60 ml.) was subjected to catalytic reductionat ambient temperature under ordinary pressure for 4 hours. Afterremoving the catalyst by filtration, the filtrate was concentrated underreduced pressure. An aqueous solution of sodium bicarbonate and ethylacetate were added to the residue, and the aqueous layer was separated.The aqueous layer was adjusted to pH 6, washed with ethyl acetate, andthen adjusted to pH 1 to 2. The aqueous layer was extracted with ethylacetate. The ethyl acetate extract was washed with an aqueous solutionof sodium chloride, dried over magnesium sulfate, and concentrated underreduced pressure. Diethyl ether (30 ml.) was added to the residue,stirred for one hour, and then precipitates were collected by filtrationto give7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer) (680 mg.), brownish yellow powder, mp. 200° to 204° C.(dec.).

I.R. ν_(max) ^(Nujol) : 3225, 1780, 1730, 1680-1650, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.65, 4.08 (2H, AB-q, J=18 Hz), 4.00 (3H, s),5.30 (1H, d, J=4.5 Hz), 5.98 (1H, dd, J=8 Hz, 4.5 Hz), 6.97 (1H, d, J=8Hz), 7.53 (1H, d, J=8 Hz), 7.87 (1H, t, J=8 Hz), 9.35 (1H, m), 9.63 (1H,d, J=8 Hz), 10.63 (1H, m).

The following compounds were prepared in substantially the same manneras that of Example 4-(1) and (2).

(3)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylicacid, mp. 173° to 175° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1770, 1720-1660, 1040, 810, 620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.61 (2H, broad s), 3.73 (3H, s), 3.95 (3H, s),5.14 (1H, d, J=5 Hz), 5.66 (1H, dd, J=5 Hz, 8 Hz), 6.9 (1H, m), 7.48(1H, d, J=8 Hz), 7.80 (1H, dd, J=8 Hz, 9 Hz), 9.3 (1H, m), 9.42 (1H, d,J=8 Hz), 10.5 (1H, m).

(4)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042cm⁻¹.

(5)7-[2-(6-aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1730, 1670 cm⁻¹.

(6)7-[2-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050cm⁻¹.

(7)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm⁻¹.

(8)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1670, 1620, 1050 cm⁻¹.

(9)7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3600-3080, 1763, 1698, 1663 cm⁻¹.

(10)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300-3100, 1780, 1710, 1660, 1610, 1540, 1370cm⁻¹.

(11)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3300, 1775, 1700-1650, 1045 cm⁻¹.

(12)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1700, 1680 cm⁻¹.

(13)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258,1050 cm⁻¹.

(14)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3100, 1780, 1682, 1668, 1260, 1050 cm⁻¹.

(15)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1760, 1680 cm⁻¹.

(16)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1720, 1670 cm⁻¹.

(17)7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043cm⁻¹.

(18)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670 cm⁻¹.

(19) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040cm⁻¹.

(20)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (a mixture of syn and anti isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1700-1620, 1240, 1040 cm⁻¹.

(21)7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3310, 1780, 1670, 1620 cm⁻¹.

(22)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3270, 1765, 1690, 1665, 1620, 1580, 1530 cm⁻¹.

(23)7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride.

I.R. ν_(max) ^(Nujol) : 3300-3100, 1785, 1660, 1390, 1050 cm⁻¹.

(24)7-[2-(4-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm⁻¹.

(25)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1670, 1625, 1590, 1550 cm⁻¹.

(26)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620 cm⁻¹.

(27)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1670, 1620 cm⁻¹.

(28)7-[2-(2-Aminopyridin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1775, 1670, 1600, 1560 cm⁻¹.

(29)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1730, 1670 cm⁻¹.

(30)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3340, 3150, 1780, 1735, 1670 cm⁻¹.

(31)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1735, 1670 cm⁻¹.

(32)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm⁻¹.

(33)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3120, 1785, 1660 cm⁻¹.

(34)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1735, 1660 cm⁻¹.

(35)7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1735, 1670 cm⁻¹.

(36)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 1780, 1670 cm⁻¹.

(37)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1690 cm⁻¹.

(38)7-[2-(6-Aminopyridin-2-yl)-2-phenoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1760, 1690, 1670 cm⁻¹.

(39)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm⁻¹.

(40)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (anti isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1780, 1680, 1630, 1520 cm⁻¹.

(41)7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350-3100, 1790, 1670, 1550, 1380, 1235, 1040cm⁻¹.

(42)7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045cm⁻¹.

(43)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 164°-171° C. (dec.).

(44)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 161°-167° C. (dec.).

(45)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer), mp. 149°-159° C. (dec.).

EXAMPLE 5

(1) A solution of7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer) (2.10 g.) and disodium2-(5-sulfido-1H-tetrazol-1-yl)acetate (2.70 g) in water (40 ml.) wasadjusted to pH 7 with sodium bicarbonate, and stirred at 65° C. for 6hours at pH 7 to 7.4. The resultant solution was washed with ethylacetate, adjusted to pH 2.5 with 10% hydrochloric acid and stirred. Theprecipitates were collected by filtration, washed with water and diethylether in turn to give7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.27 g.), mp. 166° to 168° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1782, 1737, 1670 (broad), 1577, 1247, 1053cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.60, 3.72 (2H, AB-q, J=18 Hz), 3.92 (3H, s),4.23, 4.45 (2H, AB-q, J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.28 (2H, s), 5.83(1H, dd, J=5 Hz, 8 Hz), 6.88 (1H, broad d, J=8 Hz), 7.50 (1H, d, J=8Hz), 7.83 (1H, t, J=8 Hz), 9.32 (1H, broad d, J=8 Hz), 9.55 (1H, broadd, J=8 Hz), 10.5-10.8 (1H, m).

The following compounds were prepared in substantially the same manneras that of Example 5-(1).

(2)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042cm⁻¹.

(3)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050cm⁻¹.

(4)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm⁻¹.

(5)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1670, 1620, 1050 cm⁻¹.

(6)7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3600-3080, 1763, 1698, 1663 cm⁻¹.

(7)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1700, 1680 cm⁻¹.

(8)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1760, 1680 cm⁻¹.

(9)7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043cm⁻¹.

(10)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670 cm⁻¹.

(11)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (a mixture of syn and anti isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1700-1620, 1240, 1040 cm⁻¹.

(12)7-[2-(Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3310, 1780, 1670, 1620 cm⁻¹.

(13)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3270, 1765, 1690, 1665, 1620, 1580, 1530 cm⁻¹.

(14)7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride.

I.R. ν_(max) ^(Nujol) : 3300-3100, 1785, 1660, 1390, 1050 cm⁻¹.

(15)7-[2-(4-Aminopyridin-2-yl)-2-methoxyminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm⁻¹.

(16)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1670, 1625, 1590, 1550 cm⁻¹.

(17)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620 cm⁻¹.

(18)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1670, 1620 cm⁻¹.

(19)7-[2-(2-Aminopyridin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1775, 1670, 1600, 1560 cm⁻¹.

(20)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm⁻¹.

(21)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1690 cm⁻¹.

(22)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm⁻¹.

(23)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (anti isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1780, 1680, 1630, 1520 cm⁻¹.

(24)7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350-3100, 1790, 1670, 1550, 1380, 1235, 1040cm⁻¹.

(25)7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045cm⁻¹.

(26)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 164°-171° C. (dec.).

(27)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 161°-167° C. (dec.).

EXAMPLE 6

To phosphoryl chloride (2.6 g.) was added N,N-dimethylformamide (4 ml.)and the mixture was stirred at 40° to 50° C. for 30 minutes, and thenmethylene chloride (20 ml.) was added thereto. To this mixture was added2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (1.9 g.) undercooling at -20° to -15° C. with stirring, and the stirring was continuedat the same temperature for 30 minutes.

On the other hand,7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid and trimethylsilylacetamide (11 g.) were added to methylenechloride (66 ml.) and the mixture was stirred at ambient temperature foran hour, and to this solution was added all at once the above activatedsolution of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acidunder cooling at -20° C. with stirring, and the stirring was continuedat the same temperature for an hour and at ambient temperature foradditional an hour. The reaction mixture was concentrated under reducedpressure and then ethyl acetate and an aqueous solution of sodiumbicarbonate were added to adjust the solution to pH 7 to 8. After theaqueous layer was separated out, a proper quantity of ethyl acetate wasadded thereto. The mixture was adjusted to pH 1 to 2 with dilutehydrochloric acid and then salted out. The ethyl acetate layer wasseparated out, washed with an aqueous solution of sodium chloride anddried over magnesium sulfate, and then evaporated to dryness underreduced pressure. The resultant foamy substance was pulverized in ethylether, collected by filtration and then dried to give7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (2.9 g.). Thus obtained product (0.6 g.) was dissolved in a mixedsolution of methanol and ethyl acetate (5 ml.) (2:1 by volume), and thesolution was poured into ethyl ether (40 ml.) and then the mixture wasallowed to stand for a while. The precipitates were collected byfiltration to give purified pale-yellowish powder of7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (a mixture of syn and anti isomers) (0.5 g.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1650-1730, 1570, 1240, 1175, 1040,720 cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm                                                            (DMSO-d.sub.6):                                                                         3.70 (2H, m)                                                                  3.92 (3H, s)                                                                  3.92 (s)                                                                                                 (3H)                                               3.99 (s)                                                                      4.20 and 4.30 (2H, ABq, J = 15Hz)                                             5.05 (d, J = 5Hz)                                                                                        (1H)                                               5.15 (d, J = 5Hz)                                                             5.60 (m)                                                                                                 (1H)                                               5.80 (d,d, J = 5Hz, 9Hz)                                                      6.90-7.60 (1H, m)                                                             8.61 (1H, d, J = 5Hz)                                                         8.76 (d, J = 9Hz)                                                                                        (1H)                                               9.51 (d, J = 9Hz)                                                             11.10 (1H, broad s)                                                 ______________________________________                                    

EXAMPLE 7

To phosphoryl chloride (1.6 g.) was added N,N-dimethylformamide (8 ml.)and the mixture was stirred at 40° C. for 30 minutes. To this mixturewas added a solution of2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetic acid (syn isomer) (2.0g.) in N,N-dimethylformamide (8 ml.) under cooling at -15° C. withstirring and the stirring was continued at -10° to -8° C. for an hour.

On the other hand,7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (3.2 g.) and trimethylsilylacetamide (11.5 g.) were added tomethylene chloride (35 ml.), and the mixture was stirred at 30° C. tillit became a solution and then cooled to -15° C.

To this solution was added the above obtained N,N-dimethylformamidesolution under cooling at -15° C. with stirring, and the stirring wascontinued at the same temperature for an hour. After the reactionmixture was poured into an aqueous solution (80 ml.) of sodiumbicarbonate (3.2 g.), the aqueous layer was separated out, washed withethyl acetate. To the aqueous solution was added ethyl acetate and themixture was adjusted to pH 3 to 4 with 5% hydrochloric acid. The ethylacetate layer was separated out and the remaining aqueous solution wasextracted twice with ethyl acetate. The ethyl acetate solution and theseextracts were combined together, dried and then evaporated to drynessunder reduced pressure. The residue was crystallized from water,collected by filtration and then dried to give7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.81 g.), mp. 132°-135° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1670, 1580, 1545 cm⁻¹.

N.M.R. δppm [acetone-d₆ and D₂ O]: 3.83 (2H, broad s), 4.00 (3H, s),4.43 (2H, broad s), 4.70-4.87 (2H, m), 5.27 (1H, d, J=5 Hz), 5.13-5.60(2H, m), 5.83-6.27 (2H, m), 7.00-8.00 (3H, m).

EXAMPLE 8-(1)

To phosphoryl chloride (1.61 g.) was added N,N-dimethylformamide (8 ml.)and the mixture was stirred at 40° C. for 30 minutes. To this mixturewas added a solution of2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetic acid (syn isomer)(2.0 g.) in N,N-dimethylformamide (8 ml.) under cooling at -15° C. withstirring, and the stirring was continued at -10° to -8° C. for 40minutes.

On the other hand,7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (3.25 g.) and trimethylsilylacetamide (10.5 g.) were added tomethylene chloride (40 ml.), and the mixture was stirred at 30° C. tillit became a solution.

To the solution was added the above obtained N,N-dimethylformaidemixture under cooling at -15° C. with stirring, and the stirring wascontinued at the same temperature for an hour. After the reactionmixture was poured into an aqueous solution (80 ml.) of sodiumbicarbonate (4.0 g.), the aqueous layer was separated out. The remainingmethylene chloride solution was extracted with an aqueous solution ofsodium bicarbonate. Thus obtained aqueous layer and extract werecombined together, and adjusted to pH 2 with 10% hydrochloric acid andthen extracted with ethyl acetate. The extract was washed with water,dried and then evaporated to dryness under reduced pressure. The residuewas pulverized in water, collected by filtration and then dried to give7-[2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (2.41 g.), mp. 123°-125° C. (dec.)

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1670, 1575, 1540 cm⁻¹.

N.M.R. δppm (acetone-d₆ and D₂ O): 3.07 (1H, t, J=2 Hz), 3.83 (2H, s),4.00 (3H, s), 4.43 (2H, s), 4.87 (2H, d, J=2 Hz), 5.27 (1H, d, J=5 Hz),6.07 (1H, d, J=5 Hz), 7.00-8.07 (3H, m).

The following compounds were obtained according to similar manners tothose of Examples 6 to 8-(1).

(2)7-[2-(2-Formamidopyridin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 138°-140° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1680, 1610, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H, broad s), 3.97 (3H, s), 4.03 (3H, s),4.40 (2H, broad s), 5.23 (1H, d, J=5 Hz), 5.90 (1H, d,d, J=5 Hz, 8 Hz),7.13-8.53 (3H, m), 9.87 (1H, d, J=8 Hz), 10.73 (1H, d, J=6 Hz).

(3)7-[2-(4-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 160°-166° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1690, 1590, 1520, 1380, 1040 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, m), 3.95 (6H, s), 4.32 (2H, broad s),5.15 (1H, d, J=4.5 Hz) 5.85 (1H, d,d, J=4.5 Hz, 8.0 Hz), 8.10-8.50 (4H,m), 9.52 (1H, d, J=8 Hz).

(4)7-[2-(6-Chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn and anti mixture).

I.R. ν_(max) ^(Nujol) : 3200-3300, 1780, 1700, 1680, 1550, 1380, 1040cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6):                                                            3.75 (2H, m)                                                                  3.98 (3H, s)                                                                  4.01 (3H, s)                                                                  4.35 (2H, m)                                                                  5.20 (1H, d, J = 4.5Hz)                                                       5.90 (1H, m)                                                                  6.80 (s)                                                                                            (1H)                                                    6.90 (s)                                                                      9.41 (d, J = 8Hz)                                                                                   (1H)                                                    9.69 (d, J = 8Hz)                                                             9.45 (1H, d, J = 10Hz)                                                        11.05 (d, J = 10Hz)                                                                                 (1H)                                                    11.43 (d, J = 10Hz)                                           ______________________________________                                    

(5)7-[2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-172° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1710, 1670, 1645, 1370, 1270, 1050,725 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.68 (2H, m), 3.94 (3H, s), 3.98 (3H, s), 4.20,4.38 (2H, AB_(q), J=14 Hz), 5.14 (1H, d, J=4.5 Hz), 5.82 (1H, d,d, J=4.5Hz, 8 Hz), 6.90 (1H, m), 7.94 (1H, d, J=8 Hz), 9.22 (1H, m), 9.52 (1H,d, J=8 Hz), 10.72 (1H, d, J=8 Hz).

(6)7-[2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 149°-155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1785, 1705, 1688, 1665, 1420, 1255, 1200,1073, 1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, m), 3.95 (3H, s), 4.01 (3H, s), 4.33(2H, broad s), 5.17 (1H, d, J=4.5 Hz), 5.87 (1H, d,d, J=4.5 Hz, 8 Hz),8.31 (1H, s), 9.18 (1H, d, J=8 Hz), 9.57 (1H, d, J=8 Hz), 10.65 (1H, d,J=8 Hz).

(7)7-[2-Ethoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 183°-186° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3300, 1790, 1730, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.25 (3H, t, J=7 Hz), 1.40 (3H, d, J=7 Hz), 3.75(1H, m), 4.15 (2H, q, J=7 Hz), 5.10 (1H, d, J=4 Hz), 5.90 (1H, d,d, J=8Hz, 4 Hz), 6.50 (1H, d, J=6 Hz), 6.70-8.20 (3H, m).

(8)7-[2-(6-Formamidopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1680, 1580, 1550 cm⁻¹.

N.M.R. δppm (acetone-d₆ and D₂ O): 0.96 (3H, t, J=7 Hz), 1.64-1.84 (2H,m), 3.72, 3.82 (2H, AB_(q), J=18 Hz), 3.96 (3H, s), 4.16 (2H, t, J=7Hz), 4.40 (2H, broad s), 5.20 (1H, d, J=5 Hz), 6.00 (1H, d, J=5 Hz),6.88-8.20 (3H, m).

(9)7-[2-Isopropoxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1680, 1580, 1540 cm⁻¹.

N.M.R. δppm (acetone-d₆ and D₂ O): 1.32 (6H, d, J=6 Hz), 3.76, 3.88 (2H,AB_(q), J=18 Hz), 3.98 (3H, s), 4.40 (2H, broad s), 4.36-4.64 (1H, m),5.24 (1H, d, J=5 Hz), 6.04 (1H, d, J=5 Hz), 6.92-8.20 (3H, m).

(10)7-[2-(6-Formamidopyridin-2-yl)-2-propoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 145°-150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1680 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.95 (3H, t, J=8 Hz), 1.45 (3H, d, J=7 Hz),1.40-1.90 (2H, m), 3.83 (1H, m), 4.17 (2H, t, J=6 Hz), 5.17 (1H, d, J=4Hz), 6.00 (1H, d,d, J=4 Hz, 8 Hz), 6.58 (1H, d, J=6 Hz), 6.80-8.20 (3H,m).

(11)7-[2-Isopropoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 160°-163° C.

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1735, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (6H, d, J=6 Hz), 1.45 (3H, d, J=7 Hz), 3.80(1H, m), 4.45 (1H, m), 5.15 (1H, d, J=4 Hz), 6.00 (1H, d,d, J=4 Hz, 8Hz), 6.58 (1H, d, J=6 Hz), 6.80-8.20 (3H, m).

(12)7-[2-Butoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 153°-155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1670, 1580, 1550 cm⁻¹.

N.M.R. δppm (acetone-d₆ and D₂ O): 0.80-1.07 (3H, m), 1.23-1.83 (4H, m),3.83 (2H, broad s), 3.97 (3H, s), 4.23 (2H, t, J=6 Hz), 4.43 (2H, broads), 5.27 (1H, d, J=5 Hz), 6.10 (1H, d, J=5 Hz), 6.97-8.00 (3H, m).

(13)7-[2-(6-Formamidopyridin-2-yl)-2-isobutoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 118°-120° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3500, 3300, 1785, 1680, 1580, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.93 (6H, d, J=6 Hz), 1.77-2.17 (1H, m), 3.70(2H, broad s), 3.93 (3H, s), 4.00 (2H, d, J=6 Hz), 4.33 (2H, broad s),5.18 (1H, d, J=5 Hz), 5.90 (1H, d,d, J=5 Hz, 9 Hz), 6.83-8.00 (3H, m).

(14)7-[2-Butoxyimino-2-(6-formamidopyridin-2-yl)-acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 155°-160° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1680 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.83-1.83 (10H, m), 3.67-4.00 (1H, m), 4.27 (3H,t, J=4 Hz), 5.22 (1H, d, J=4 Hz), 6.03 (1H, d,d, J=4 Hz, 8 Hz),

6.62 (1H, d, J=6 Hz), 7.00-8.50 (3H, m).

(15)7-[2-(6-Formamidopyridin-2-yl)-2-isobutoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 152°-154° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1675 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 0.90 (6H, d, J=6 Hz), 1.42 (3H, d, J=6 Hz), 2.00(1H, m), 3.80 (1H, m), 3.90 (2H, d, J=6 Hz), 5.10 (1H, d, J=4 Hz), 5.95(1H, d,d, J=4 Hz, 8 Hz), 6.50 (1H, d, J=6 Hz), 6.80-8.20 (3H, m).

(16)7-[2-Allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer) mp. 128°-132° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1730, 1670 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.45 (3H, d, J=7 Hz), 3.85 (1H, m), 4.70 (2H, d,J=5 Hz), 5.20 (1H, d, J=4 Hz), 5.20-5.50 (2H, m), 5.80-6.20 (1H, m),6.00 (1H, d,d, J=4 Hz, 8 Hz), 6.60 (1H, d, J=6 Hz), 6.80-8.20 (3H, m).

(17)7-[2-(6-Formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 134°-137° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1730, 1670 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.45 (3H, d, J=7 Hz), 3.50 (1H, t, J=2 Hz), 3.80(1H, m), 4.85 (2H, d, J=2 Hz), 5.15 (1H, d, J=4 Hz), 6.00 (1H, d,d, J=4Hz, 8 Hz), 6.58 (1H, d, J=6 Hz), 6.80-8.20 (3H, m).

(18)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1790, 1690 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.70 (2H, broad s), 3.93 (3H, s), 4.32 (2H,broad s), 4.70, 4.95 (2H, AB_(q), J=9 Hz), 5.15 (1H, d, J=4 Hz), 5.88(1H, d,d, J=4 Hz, 8 Hz), 7.00-8.00 (3H, m), 9.33 (1H, m), 9.67 (1H, d,J=8 Hz), 10.60 (1H, m).

(19)7-[2-(6-Formamidopyridin-2-yl)-2-phenoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150°-155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1720, 1650 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 1.50 (3H, d, J=7 Hz), 3.90 (1H, m), 5.25 (1H, d,J=4 Hz), 6.10 (1H, d,d, J=4 Hz, 8 Hz), 6.60 (1H, d, J=6 Hz), 7.0-8.2 (8H, m), 9.86 (1H, d, J=8 Hz), 10.73 (1H, d, J=8 Hz).

(20)7-[2-(6-Formamidopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1680, 1250, 1175, 1035 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.75 (2H, broad s), 3.98 (6H, s), 4.35 (2H,broad s), 5.22 (1H, d, J=5 Hz), 5.87 (1H, d,d, J=5 Hz, 8 Hz), 7.8-8.5(3H, m), 9.83 (1H, d, J=8 Hz), 10.87 (1H, d, J=7 Hz).

(21)7-[2-(6-Formamidopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (anti isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1680-1710, 1600, 1240, 1050 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.74 (2H, broad s), 3.96 (3H, s), 4.00 (3H, s),4.00, 4.28 (2H, AB_(q), J=13 Hz), 5.16 (1H, d, J=5 Hz), 5.72 (1H, d,d,J=5 Hz, 8 Hz), 7.80-8.50 (3H, m), 9.28 (1H, d, J=8 Hz), 10.80 (1H, d,J=6 Hz).

EXAMPLE 9

(1) Phosphoryl chloride (500 mg.) was added dropwise to a suspension of2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (250mg.) in ethyl acetate (5 ml.) at 0° to 6° C. with stirring and thestirring was continued at the same temperature for 45 minutes. To thissolution was added dropwise N,N-dimethylformamide (0.7 ml.) over aperiod of 6 minutes at 0° to 6° C. with stirring, and the stirring wascontinued at the same temperature for 40 minutes. To the resultantsolution was added all at once a solution of7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (365 mg.) and trimethylsilylacetamide (1.5 g.) in ethyl acetate (7ml.) under cooling at -20° C., and the mixture was stirred at 0° to 6°C. for an hour. The reaction mixture was poured into water (20 ml.) andadjusted to pH 4 with an aqueous solution of sodium bicarbonate. Theaqueous layer was separated out and the remaining organic layer wasextracted with water. The aqueous layers were combined together and theethyl acetate remained in the aqueous solution was removed therefromunder reduced pressure. The aqueous solution was subjected to columnchromatography on a non-ionic adsorption resin, "Diaion HP-20" (TradeMark, manufactured by Mitsubishi Chemical Industry Ltd.) (20 ml.). Afterthe column was washed with water, elution was carried out with 5-10%aqueous methanol (100 ml.), 20% aqueous methanol (150 ml.) and 20 to 30%aqueous methanol (150 ml.) in turn, and the fractions containing thedesired compound were collected and evaporated to dryness under reducedpressure. The resultant residue was lyophilized to give 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (110 mg.), mp. 155° to 158° C.

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1630-1690, 1590, 1040, 840cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.65 (2H, m), 3.94 (3H, s), 4.32 (2H, broad s),5.11 (1H, d, J=5 Hz), 5.80 (1H, d,d, J=5 Hz, 8 Hz), 6.44 (1H, d, J=6Hz), 7.04 (2H, broad s), 8.10 (1H, d, J=6 Hz), 9.43 (1H, d, J=8 Hz).

The following compounds were obtained according to similar manner tothat of Example 9-(1).

(2)7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 149°-151° C. (dec.).

(3)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 163°-165° C. (dec.).

(4)7-[2-(2-Aminopyridin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 175°-177° C. (dec.).

(5)7-[2-(4-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 163°-167° C. (dec.).

(6)7-[2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride, mp. 170°-180° C.

(7)7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride (syn isomer), mp. 155°-160° C. (dec.).

(8)7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-metoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 139°-144° C. (dec.).

(9)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190°-195° C. (dec.).

(10) 7-[2-(6-aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), 138°-140° C. (dec.).

(11)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 149°-151° C. (dec.).

(12)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190°-195° C. (dec.).

(13)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185°-188° C. (dec.).

(14)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 108°-110° C. (dec.).

(15)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 140°-142° C. (dec.).

(16)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 200°-205° C. (dec.).

(17)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175°-180° C. (dec.).

(18)7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 168°-173° C. (dec.).

(19)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-170° C. (dec.).

(20)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-170° C. (dec.).

(21)7-[2-(6-Aminopyridin-2-yl)-2-phenoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 145°-147° C. (dec.).

(22)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-167° C. (dec.).

(23)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (anti isomer), mp. 153°-155° C. (dec.).

(24)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 164°-171° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1620-1690, 1585, 1540, 1250,1060, 1040, 895, 830, 720 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 3.73 (2H, broad s), 3.95 (3H, s), 4.28, 4.65(2H, ABq, J=13 Hz), 5.18 (1H, d, J=5 Hz), 5.87 (1H, d, d, J=5 Hz, 8 Hz),6.48 (1H, d, J=7 Hz), 7.05 (2H, broad s), 8.15 (1H, d, J=7 Hz), 9.47(1H, d, J=8 Hz), 9.63 (1H, s).

(25)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 161°-167° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1620-1690, 1585, 1250, 1045,840, 720 cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 2.70 (3H, s), 3.70 (2H, broad s), 3.97 (3H, s),4.21, 4.58 (2H, ABq, J=13 Hz), 5.22 (1H, d, J=5 Hz), 5.81 (1H, d, d, J=5Hz), 5.81 (1H, d, d, J=5 Hz, 8 Hz), 6.47 (1H, d, J=7 Hz), 7.05 (2H,broad s), 8.12 (1H, d, J=7 Hz), 9.47 (1H, d, J=8 Hz).

(26)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer), mp 149°-159° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1730, 1630-1680, 1040, 725cm⁻¹.

N.M.R. δ ppm (DMSO-d₆): 2.03 (3H, s), 3.36, 3.62 (2H, ABq, J=18 Hz),3.93 (3H, s), 4.7, 5.0 (2H, ABq, J=12 Hz), 5.10 (1H, d, J=4.5 Hz), 5.77(1H, d, d, J=4.5 Hz, 8.0 Hz), 6.43 (1H, d, J=6.0 Hz), 8.10 (1H, d, J=6.0Hz), 9.40 (1H, d, J=8.0 Hz).

(27)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3360, 3220, 1780, 1670, 1620, 1585, 1544, 1042cm⁻¹.

(28)7-[2-(6-Aminopyridin-2-yl)-2-methoximinoacetamido]-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1730, 1670 cm⁻¹.

(29)7-[2-(6-Aminopyridin-2-yl)-2-methoximinoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1780, 1670, 1622, 1590, 1550, 1050cm⁻¹.

(30)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3500, 3400, 3230, 1770, 1670, 1620, 1040 cm⁻¹.

(31)7-[2-(6-Aminopyridin-2-yl)-2-methoximinoacetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1670, 1620, 1050 cm⁻¹.

(32)7-[2-(6-Aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3600-3080, 1763, 1698, 1663 cm⁻¹.

(33)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300-3100, 1780, 1710, 1660, 1610, 1540, 1370cm⁻¹.

7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3300, 1775, 1700-1650, 1045 cm⁻¹.

(35)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1700, 1680 cm⁻¹.

(36)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400-3100, 1780, 1730, 1665, 1550, 1295, 1258,1050 cm⁻¹.

(37)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid hydrochloride (syn isomer).

I.R. ν_(max) ^(Nujol) : 3100, 1780, 1682, 1668, 1260, 1050 cm⁻¹.

(38)7-[2-(6-Aminopyridin-2-yl)-2-hydroximinoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1760, 1680 cm⁻¹.

(39)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1720, 1670 cm⁻¹.

(40)7-[2-(2-Aminopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1790, 1693, 1660, 1630, 1525, 1043cm⁻¹.

(41)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670 cm⁻¹.

(42) 7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350-3220, 1780, 1740, 1680-1655, 1380, 1040cm⁻¹.

EXAMPLE 10

Conc. hydrochloric acid (0.36 ml) was added to a solution of7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (1.9 g) in methanol (38 ml), and the mixture was stirred at ambienttemperature for 5.5 hours. The reaction mixture was concentrated, andthe concentrate was diluted with water and then washed with ethylacetate. After the ethyl acetate in the aqueous solution was removed bydistillation, the aqueous solution was subjected to columnchromatography on a macroporous, non-ionic adsorption resin, "DiaionHP-20" (Trade mark, manufactured by Mitsubishi Chemical Industries Ltd.)(110 ml). Elution was carried out with water (400 ml), 10% aqueousmethanol (100 ml.), 20% aqueous methanol (200 ml.) and then 30% aqueousmethanol (2 l.), and the fractions containing the desired compound werecollected. The combined fractions were evaporated to dryness underreduced pressure to give powders (1.0 g.) of7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (a mixture of syn and anti isomer), mp. 150°-160° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1620-1700, 1240, 1040 cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6):                                                            3.72 (2H, broad s),                                                           3.98 (6H, s)                                                                  4.34 (2H, broad s)                                                            5.08 (d, J = 4H)                                                                                   (1H)                                                     5.15 (d, J = 4Hz)                                                             5.60-6.00 (1H, m)                                                             6.45 (1H, d, J = 6Hz)                                                         7.00 (2H, m)                                                                  8.12 (1H, d, J = 6Hz)                                                         8.87 (d, J = 8Hz)                                                                                  (1H)                                                     9.43 (d, J = 8Hz)                                             ______________________________________                                    

EXAMPLE 11

Conc. hydrochloric acid (0.31 ml.) was added to a solution of7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.75 g.) in methanol (7 ml.), and the mixture wasstirred at ambient temperature for 30 minutes. The methanol was removedby distillation from the reaction mixture, and the remaining aqueoussolution was diluted with water (80 ml.) and then adjusted to pH 2-3with an aqueous solution of sodium bicarbonate. The aqueous solution wassubjected to column chromatography on a macroporous, non-ionicadsorption resin "Diaion HP-20" (Trade Mark, manufactured by MitsubishiChemical Industries Ltd.) (50 ml.). After the column was washed withwater (1 l.), elution was carried out with 50% aqueous methanol (1 l.)and fractions containing the desired compound were collected. Themethanol was removed by distillation from the combined fractions underreduced pressure and the resultant aqueous solution was lyophilized togive7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.13 g.), mp. 149°-151° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3310, 1780, 1670, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, broad s), 3.93 (3H, s), 4.33 (2H, broads), 4.67 (2H, d, J=5 Hz), 5.17-5.57 (2H, m), 5.10 (1H, d, J=5 Hz), 5.80(1H, d,d, J=5 Hz, 9 Hz), 5.83-6.27 (1H, m), 6.50 (1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.43 (1H, t, J=8 Hz), 9.47 (1H, d, J=9 Hz).

EXAMPLE 12

Conc. Hydrochloric acid (0.43 ml.) was added to a solution of7-[2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (2.35 g.) in methanol (15 ml.), and the mixture wasstirred at ambient temperature for 30 minutes. The methanol was removedby distillation under reduced pressure from the reaction mixture, andthe remaining aqueous solution was diluted with water (100 ml.) and thenadjusted to pH 2 with an aqueous solution of sodium bicarbonate. Theprecipitating crystals were collected by filtration, washed with waterand then dried to give7-[2-(6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.05 g.), mp. 163°-165° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3270, 1765, 1690, 1665, 1620, 1580, 1530 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.48 (1H, t, J=2 Hz), 3.62, 3.76 (2H, AB_(q),J=18 Hz), 3.90 (3H, s), 4.26, 4.34 (2H, AB_(q), J=13 Hz), 4.76 (2H, d,J=2 Hz), 5.12 (1H, d, J=5 Hz), 5.80 (1H, d,d, J=5 Hz, 9 Hz), 6.52 (1H,d, J=8 Hz), 6.88 (1H, d, J=8 Hz), 7.42 (1H, t, J=8 Hz), 9.54 (1H, d, J=9Hz).

EXAMPLE 13-(1)

Conc. hydrochloric acid (242 mg.) was added to a solution of7-[2-(6-chloro-2-formamidopyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (1.2 g.) in methanol (12 ml.), and the mixture was stirred atambient temperature for 5 hours. The reaction mixture was evaporated todryness under reduced pressure to give a foamy residue, which waspulverized with ethyl ether. This powder (1.1 g.) was dissolved inmethanol (6 ml.), and to ethyl ether (50 ml.) was added dropwise themethanol solution. The precipitates were collected by filtration andthen dried to give7-[2-(2-amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride (0.95 g.).

I.R. ν_(max) ^(Nujol) : 3100-3300, 1785, 1660, 1390, 1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.75 (2H, m), 3.95 (3H, s), 4.00 (3H, s), 4.24,4.40 (2H, AB_(q), J=14 Hz), 5.18 (1H, d, J=4.5 Hz), 5.79 (1H, d,d, J=4.5Hz, 8.0 Hz), 6.28 (1H, s), 8.00-10.00 (2H, broad s), 9.96 (1H, d, J=8Hz).

The following compounds were obtained according to similar manners tothose of Examples 10 and 13-(1).

(2)7-[2-(4-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 163°-167° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3230, 1778, 1650, 1600, 1380, 1050 cm⁻¹.

N.M.R. δppm (DMSO-d₆ and D₂ O): 3.64 (2H, m), 3.97 (6H, s), 4.32 (2H,broad s), 5.12 (1H, d, J=4.5 Hz), 5.80 (1H, d,d, J=4.5 Hz, 8 Hz), 6.60(1H, d,d, J=2 Hz, 7 Hz), 6.97 (1H, d, J=2 Hz), 8.00 (1H, d, J=7 Hz),9.52 (1H, d, J=8 Hz).

(3)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 138°-140° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1670, 1625, 1590, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.9 (3H, t, J=8 Hz), 1.67 (2H, m), 3.7 (2H, broads), 3.93 (3H, s), 4.07 (2H, t, J=8 Hz), 4.30 (2H, broad s), 5.13 (1H, d,J=5 Hz), 5.83 (1H, d,d, J=5 Hz, 9 Hz), 6.50 (1H, d, J=8 Hz), 6.90 (1H,d, J=8 Hz), 7.47 (1H, t, J=8 Hz), 9.30 (1H, d, J=9 Hz).

(4)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 149°-151° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.27 (6H, d, J=6 Hz), 3.70 (2H, broad s), 3.97(3H, s), 4.33 (2H, broad s), 4.35 (1H, m), 5.17 (1H, d, J=5 Hz), 5.87(1H, d,d, J=5 Hz, 9 Hz), 6.50 (1H, d, J=8 Hz), 6.93 (1H, d, J=8 Hz),7.47 (1H, t, J=8 Hz), 9.43 (1H, d, J=9 Hz).

(5)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 140°-142° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1670, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.88 (6H, d, J=7 Hz), 1.96 (1H, m), 3.68 (2H,broad s), 3.88 (2H, d, J=7 Hz), 3.92 (3H, s), 4.24, 4.36 (2H, AB_(q),J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.84 (1H, d,d, J=5 Hz, 9 Hz), 6.48 (1H,d, J=8 Hz), 6.88 (1H, d, J=8 Hz), 7.40 (1H, t, J=8 Hz), 9.44 (1H, d, J=9Hz).

(6)7-[2-(2-Aminopyridin-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 175°-177° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1775, 1670, 1600, 1560 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H, broad s), 3.98 (6H, s), 4.35 (2H, broads), 5.18 (1H, d, J=5 Hz), 5.83 (1H, d,d, J=5 Hz, 8 Hz), 6.67-6.80 (2H,m), 8.00 (1H, d, J=6 Hz), 9.79 (1H, d, J=8 Hz).

(7)7-[2-(6-Aminopyridin-2-yl)-2-ethoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190°-195° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1730, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.33 (3H, t, J=7 Hz), 1.43 (3H, d, J=7 Hz), 3.90(1H, m), 4.35 (2H, q, J=7 Hz), 5.17 (1H, d, J=4 Hz), 5.92 (1H, d,d, J=4Hz, 8 Hz), 6.58 (1H, d, J=6 Hz), 6.73 (1H, d, J=7 Hz), 7.17 (1H, d, J=8Hz), 7.95 (1H, d,d, J=7 Hz, 8 Hz), 9.93 (1H, d, J=8 Hz).

(8)7-[2-(6-Aminopyridin-2-yl)-2-propoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 190°-195° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3340, 3150, 1780, 1735, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.85 (3H, t, J=8 Hz), 1.40 (3H, d, J=7 Hz), 1.70(2H, m), 3.80 (1H, m), 4.15 (2H, t, J=6 Hz), 5.10 (1H, d, J=4 Hz), 5.90(1H, d,d, J=4 Hz, 8 Hz), 6.54 (1H, d, J=6 Hz), 6.74 (1H, d, J=7 Hz),6.85 (1H, d, J=7 Hz), 7.68 (1H, t, J=7 Hz), 9.68 (1H, d, J=8 Hz).

(9)7-[2-(6-Aminopyridin-2-yl)-2-isopropoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 185°-188° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1735, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.37 (6H, d, J=6 Hz), 1.47 (3H, d, J=6 Hz), 3.92(1H, m), 4.58 (1H, m), 5.20 (1H, d, J=4 Hz), 5.93 (1H, d,d, J=4 Hz, 8Hz), 6.60 (1H, d, J=6 Hz), 6.77 (1H, d, J=7 Hz), 7.08 (1H, d, J=8 Hz),7.90 (1H, d,d, J=7 Hz, 8 Hz), 9.87 (1H, d, J=8 Hz).

(10)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 108°-110° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1670, 1620, 1585, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.90 (3H, t, J=7 Hz), 1.80-1.16 (4H, m), 3.70(2H, broad s), 3.92 (3H, s), 4.16 (2H, t, J=7 Hz), 4.30 (2H, broad s),5.14 (1H, d, J=5 Hz), 5.78 (1H, d,d, J=5 Hz, 9 Hz), 6.58 (1H, d, J=8Hz), 6.86 (1H, d, J=8 Hz), 7.48 (1H, t, J=8 Hz), 9.50 (1H, d, J=9 Hz).

(11)7-[2-(6-Aminopyridin-2-yl)-2-butoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 200°-205° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3120, 1785, 1660 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.90 (3H, t, J=7 Hz), 1.45 (3H, d, J=6 Hz),1.20-1.80 (4H, m), 3.85 (1H, m), 4.25 (2H, t, J=6 Hz), 5.12 (1H, d, J=5Hz), 5.90 (1H, d,d, J=5 Hz, 8 Hz), 6.56 (1H, d, J=5 Hz), 6.70 (1H, d,J=7 Hz), 7.05 (1H, d, J=7 Hz), 7.82 (1H, t, J=7 Hz), 9.80 (1H, d, J=8Hz).

(12)7-[2-(6-Aminopyridin-2-yl)-2-isobutoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175°-180° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1735, 1660 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.95 (6H, d, J=6 Hz), 1.48 (3H, d, J=7 Hz), 2.08(1H, m), 3.92 (1H, m), 4.08 (2H, d, J=7 Hz), 5.20 (1H, d, J=4 Hz), 5.95(1H, d,d, J=4 Hz, 8 Hz), 6.62 (1H, d, J=6 Hz), 6.80 (1H, d, J=7 Hz),7.07 (1H, d, J=8 Hz), 7.88 (1H, d,d, J=7 Hz, 8 Hz), 9.87 (1H, d, J=8Hz).

(13)7-[2-Allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 168°-173° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3150, 1795, 1735, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.47 (3H, d, J=7 Hz), 3.90 (1H, m), 4.83 (2H, d,J=5 Hz), 5.20 (1H, d, J=4 Hz), 5.23-5.66 (2H, m), 5.95 (1H, d,d, J=4 Hz,8 Hz), 5.83-6.30 (1H, m), 6.60 (1H, d, J=6 Hz), 6.77 (1H, d, J=7 Hz),7.10 (1H, d, J=7 Hz), 7.93 (1H, t, J=7 Hz), 9.93 (1H, d, J=8 Hz).

(14)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 1780, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.47 (3H, d, J=7 Hz), 3.58 (2H, t, J=2 Hz), 3.87(1H, m), 4.88 (1H, d, J=2 Hz), 5.17 (1H, d, J=4 Hz), 5.93 (1H, d,d, J=4Hz, 8 Hz), 6.58 (1H, d, J=6 Hz), 6.66 (1H, d, J=8 Hz), 6.70 (1H, d, J=8Hz), 7.68 (1H, t, J=8 Hz), 9.77 (1H, d, J=8 Hz).

(15)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 1780, 1690 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.72 (2H, broad s), 3.95 (3H, s), 4.32 (2H, broads), 4.66, 4.92 (2H, AB_(q), J=9 Hz), 5.17 (1H, d, J=4 Hz), 5.83 (1H,d,d, J=4 Hz, 8 Hz), 6.32 (1H, d, J=8 Hz), 6.90 (1H, d, J=8 Hz), 7.55(1H, t, J=8 Hz), 9.68 (1H, d, J=8 Hz).

(16)7-[2-(6-Aminopyridin-2-yl)-2-phenoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp. 145°-147° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1760, 1690, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.50 (3H, d, J=7 Hz), 3.90 (1H, m), 5.23 (1H, d,J=4 Hz), 6.05 (1H, d,d, J=4 Hz, 8 Hz), 6.60 (1H, d, J=6 Hz), 6.73 (1H,d, J=7.5 Hz), 7.13 (1H, d, J=7.5 Hz), 7.00-7.50 (5H, m), 7.63 (1H, d,J=7.5 Hz), 9.88 (1H, d, J=8 Hz).

(17)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 165°-167° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3220, 1780, 1680, 1630, 1590, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.75 (2H, broad s), 3.90 (3H, s), 3.97 (3H, s),4.35 (2H, broad s), 5.17 (1H, d, J=5 Hz), 5.82 (1H, d,d, J=5 Hz, 8 Hz),6.57 (1H, d, J=9 Hz), 7.67 (1H, d,d, J=2 Hz, 9 Hz), 8.03 (1H, d, J=2Hz), 9.73 (1H, d, J=8 Hz).

(18)7-[2-(6-Aminopyridin-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (anti isomer), mp 153°-155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1780, 1680, 1630, 1520 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H, broad s), 3.97 (6H, s), 4.35 (2H, broads), 5.17 (1H, d, J=5 Hz), 5.72 (1H, d,d, J=5 Hz, 8 Hz), 6.62 (1H, d, J=9Hz), 7.75 (1H, d,d, J=2 Hz, 9 Hz), 8.25 (1H, d, J=2 Hz), 9.25 (1H, d,J=8 Hz).

(19)7-[2-(6-Amino-3-chloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid hydrochloride (syn isomer), mp. 155°-160° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3100-3350, 1790, 1670, 1550, 1380, 1235, 1040cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (2H, m), 3.94 (3H, s), 4.03 (3H, s), 4.21,4.37 (2H, AB_(q), J=14 Hz), 5.14 (1H, d, J=4.5 Hz), 5.80 (1H, d,d, J=4.5Hz, 8 Hz), 6.97 (1H, d, J=10 Hz), 7.80 (1H, d, J=10 Hz), 7.50-9.00 (2H,m), 9.70 (1H, d, J=8 Hz).

(20)7-[2-(6-Amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 139°-144° C. (dec.).

I.R. δ_(max) ^(Nujol) : 3300, 1785, 1730, 1660, 1545, 1380, 1235, 1045cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H, m), 3.98 (6H, s), 4.35 (2H, broad s),5.17 (1H, d, J=4.5 Hz), 5.81 (1H, d,d, J=4.5 Hz, 8 Hz), 7.87 (1H, s),7.50-8.20 (2H, m), 9.43 (1H, d, J=8 Hz).

(21)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 164°-171° C. (dec.).

(22)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 161°-167° C. (dec.).

(23)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer), mp 149°-159° C. (dec.).

EXAMPLE 14

(1) A mixture of N,N-dimethyl formamide (12 ml) and phosphoryl chloride(1.84 g) was stirred for 30 minutes at ambient temperature. To themixture were added methylene chloride (12 ml) and2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer)(1.91 g) at -5° to 0° C., and then the reaction mixture was stirred foran hour at the same temperature.

On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid(4.36 g) and trimethylsilyl acetamide (12 g) in methylene chloride (120ml) was warmed to make a clear solution. The solution was cooled to -10°C. and added to the activated acid solution obtained above.

The reaction mixture was stirred for 40 minutes at 0° C., and thenpoured into a cold aqueous solution of sodium bicarbonate. The aqueouslayer was separated out, adjusted to pH 2 with 10% hydrochloric acid andextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and evaporated to dryness. The residue was trituratedwith diethyl ether to give an amorphous precipitate (3.6 g) of7-[2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. δ_(max) ^(Nujol) : 3250, 1780, 1660, 1570 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (3H,t,J=7 Hz), 3.27 (2H, board s), 4.27(2H,q,J=7 Hz), 4.30, 4.57 (2H,ABq,J=13 Hz), 5.18 (1H,d,J=5 Hz), 5.88(1H, dd, J=5 Hz, 8 Hz), 7.1-7.5 (1H,m), 8.67 (1H,d,J=6 Hz), 8.9-9.2(1H,m), 9.45 (1H,d,j=8 Hz), 9.52 (1H,s), 11.10 (1H,d,J=7 Hz).

The following compounds were obtained according to the similar manner tothat of Example 14-(1).

(2)7-[2-(4-Formamidopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 170°-175° C. (dec.).

I.R.ν_(max) ^(Nujol) : 3250, 3100, 1780, 1710, 1670, 1615, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.93 (3H,t,J=7 Hz), 1.4-1.9 (2H,m), 3.72(2H,broad s), 4.20 (2H,t,J=7 Hz), 4.33, 4.58 (2H, ABq, J=13 Hz), 5.20(1H,d,J=6 Hz), 5.92 (1H, d,d,J=5 Hz, 8 Hz), 7.0-7.7 (1H,m), 8.67(1H,d,J=6 Hz), 8.8-9.2 (1H,m), 9.47 (1H,d,J=8 Hz), 9.53 (1H,s), 11.23(1H,d,J=6 Hz).

(3)7-[2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 130°-133° C. (dec.).

I.R.ν_(max) ^(Nujol) : 3250, 1780, 1720, 1660, 1570 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H,broad s), 4.80 (2H,d,J=5 Hz), 5.20 (1H,d, J=5 Hz), 5.1-5.6 (2H, m), 5.90 (1H,d,d,J=5 Hz, 8 Hz), 5.7-6.3 (1H,m), 7.0-8.7 (1H,m), 8.68 (1H,d, J=6 Hz), 8.8-9.3 (1H,m), 9.53 (1H, d,J=8Hz), 9.57 (1H,s), 11.23 (1H, d, J=6 Hz).

(4)7-[2-Benzyloxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 143°-145° C. (dec.).

I.R.ν_(max) ^(Nujol) : 3300, 1785, 1720, 1670, 1575 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.63 (2H, broad s), 4.28, 4.52 (2H,ABq,J=13 Hz),5.13 (1H,d,J=5 Hz), 5.27 (2H,s), 5.85(1H,d,d,J=5 Hz, 8 Hz), 7.32 (5H,s),7.2-7.6 (1H,m), 8.60 (1H,d,J=6 Hz), 8.8-9.2 (1H,m), 9.52 (1H,s), 9.55(1H,d,J=8 Hz), 11.30 (1H,d,J=6 Hz).

(5)7-[2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-[1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1700-1670, 1580, 1380, 1260, 815cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.72 (2H, broad s), 3.95 (3H,s), 4.20, 4.50 (2H,ABq, J=13 Hz), 4.9-6.6(7H,m), 6.85-9.42(5H,m), 10.5(1H,m).

(6)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]cephalosporanicacid (syn isomer), which starts to decompose at 120° C.

I.R. ν_(max) ^(Nujol) : 3310, 1788, 1718, 1673 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.00 (3H,s), 3.53 (2H, broad s), 4.5-5.0 (4H,m),5.15 (1H,d,J=5 Hz), 5.88 (1H,d,d, J=5 Hz, 8 Hz), 6.7-8.1 (3H,m), 9.27(1H,broad d, J=10 Hz), 9.62 (1H,d,J=8 Hz), 10.40-10.85 (1H, m).

(7)7-[2-Allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp. 170°-180° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1788, 1720-1680 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.43 (9H,s), 3.72 (2H, broad s), 4.1-4.9 (6H,m),5.1-6.3 (5H,m), 6.75-8.1 (3H,m), 9.1-9.5 (1H,m), 9.58 (1H,d,J=8 Hz),10.4-10.8 (1H,m).

(8)7-[2-(6-Formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 152°-156° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1780, 1670, 1580 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.5 (1H,m), 3.7 (2H,m), 4.25, 4.62 (2H,ABq,J=13Hz), 4.8 (2H,m), 5.17(1H,d,J=4.5 Hz), 6.22 (1H,d,d,J=4.5 Hz,8 Hz),7.0-9.4 (2H, m), 7.5 (1H,d,J=7 Hz), 7.85 (1H,t, J=7 Hz), 9.57(1H,s),9.4-9.5 (1H, m), 10.6 (1H,m).

(9) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1710, 1680, 1570 cm⁻¹.

(10) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]cephalosporanic acid (syn isomer), mp 150°-154° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1700, 1670, 1590 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.05 (3H,s), 3.58 (2H, broad s), 4.00 (3H,s),4.73, 5.00 (2H,ABq,J=13 Hz), 5.20 (1H,d,J=4 Hz), 5.90 (1H,d,d,J=4 Hz,8Hz), 7.40 (1H, broad s), 8.68 (1H,d,J=5 Hz), 9.07 (1H,broad s), 9.53(1H,d,J=8 Hz), 11.23 (1H,d,J=8 Hz).

(11) A mixture of N,N-dimethylformamide (14 ml) and phosphoryl chloride(2.5 g) was stirred for 30 minutes at 40° C. To the mixture were addedmethylene chloride (14 ml) and2-(2,2-dichloroacetoxyimino)-2-(6-formamidopyridin-2-yl)acetic acid (synisomer) (5.3 g) at -20° C., and then the reaction mixture was stirredfor 30 minutes at -15° to -10° C.

On the other hand, a mixture of7-amino-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (5.89 g) and trimethylsilyl acetamide (16 g) is methylene chloride(150 ml) was warmed to make a clear solution. The solution was cooled to-15° C. and added all at once to the activated acid solution preparedabove. The reaction mixture was stirred for 30 minutes at -15° to 0° C.and for additional 30 minutes at ambient temperature. The solvent wasremoved by distillation from the reaction mixture under reduced pressureto give a residue, to which ethyl acetate (150 ml) and water (100 ml)were added, and then the mixed solution was adjusted to pH 3 with anaqueous solution of sodium bicarbonate. The organic layer was separatedout, washed two times with an aqueous solution of sodium chloride anddried over magnesium sulfate, and then evaporated to dryness to give abrownish oil. This oil was washed three times with diethyl ether (70 ml)and triturated with diisopropyl ether to give a powder of7-[2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 74°-84° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1700-1675, 1580, 1380, 1260, 810cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.8-1.8 (11H,m), 3.7 (2H,m), 4.3 (4H,m), 5.18(1H,d,J=4.5 Hz), 5.95 (1H,d,d,J=4.5 Hz, 8 Hz), 7.5-9.43 (5H,m), 10.6(1H,m).

The following compound was obtained according to the similar manner tothat of Example 14-(11).

(12)7-[2-(6-Formamidopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 88°-91° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1785, 1700-1660, 1580, 1380, 1260, 815cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.63 (2H, broad s), 4.13, 4.43 (2H, ABq,J=13 Hz),4.93 (2H,m), 5.0-5.2 (1H,m), 5.25 (2H,m), 5.67-6.16 (2H,m), 6.38-8.08(3H,m), 9.3 (1H,d, J=8 Hz), 10.55 (1H,m).

(13) A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic aciddihydrate (syn isomer) (1.62 g) and phosphoryl chloride (4.3 g) inmethylene chloride (10 ml) was stirred for 30 minutes at 0° to 5° C. Tothe above mixture was added dropwise N,N-dimethylformamide (5.3 ml) andthe resultant mixture was stirred for 30 minutes at 0° to 5° C.

On the other hand, a mixture of7-amino-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (2.5 g) and trimethylsilyl acetamide (10 g) in methylene chloride(35 ml) was warmed to make a clear solution. The solution was cooled to-5° C. and added to the activated acid solution obtained above.

The reaction mixture was stirred for 30 minutes at 5° to 10° C. and foradditional 30 minutes at ambient temperature and then poured into a coldaqueous solution of sodium bicarbonate. The aqueous layer was separatedout, adjusted to pH 3 with 10% hydrochloric acid, washed with ethylacetate and then subjected to column chromatography over nonionicadsorption resin, "Diaion HP20" (Trade Mark, manufactured by MitsubishiChemical Industries Ltd.) (70 ml). The column was washed with water andeluted with 30% aqueous methanol. The eluent containing a desiredcompound was evaporated to remove the methanol under reduced pressureand then lyophilized to give

7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.58 g), mp 151°-156° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1680˜1640 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.7 (2H,m), 3.95 (3H, s), 4.23, 4.48 (2H,ABq,J=13Hz), 4.8-5.4(5H,m), 5.7-6.2 (2H,m), 6.45 (1H,d,J=7 Hz), 7.05 (2H, broads), 8.10 (1H,d,J=7 Hz), 9.45 (1H,d,J=8 Hz).

(14) A mixture of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (2.32 g) and phosphoryl chloride (4.6 g) in methylenechloride (15 ml) was stirred for 30 minutes at 3° C. To the mixture wasadded dropwise a solution of N,N-dimethylformamide (3.0 ml) in methylenechloride (15 ml) and stirred for 40 minutes at 3° C. A solution of4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.02 g) and trimethylsilylacetamide (15 g) in methylene chloride (60 ml) was cooled to -5° C. andadded to the activated acid solution obtained above. The mixture wasstirred for 30 minutes at 3° to 5° C. and for additional 30 minutes atambient temperature. The solvent was evaporated to dryness and theresidue was dissolved in ethyl acetate (200 ml). The solution was washedwith an aqueous solution of sodium bicarbonate and water, dried overanhydrous magnesium sulfate and evaporated to dryness. The residue waswashed with diethyl ether to give 4-nitrobenzyl7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate(syn isomer) (3.1 g) as a powder, mp 125°-131° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3500, 3400, 3250, 1790, 1720, 1690, 1640, 1525,1040, 855, 740 cm⁻¹.

The following compounds were obtained according to the similar manner tothose of Examples 1-(13) and (14).

(15)7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 175°-181° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3300, 1780, 1665, 1635, 1590 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.45 (3H,d,J=7 Hz), 3.78 (1H,d,J=7 Hz), 3.95(3H,s), 5.10 (1H,d,J=4.5 Hz), 5.93 (1H, d,d,J=4.5 Hz,8 Hz), 6.45 (1H,d,J=7 Hz), 6.57 (1H,d,J=6 Hz), 7.05 (2H, broad s), 8.10 (1H,d, J=6 Hz),9.41 (1H,d,J=8 Hz).

(16)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 169°-175° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3210, 1765, 1680-1630, 1580, 1375, 1040,920, 720 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.03 (3H,s), 3.25, 3.66 (2H, ABq, J=18 Hz), 3.95(3H,s), 5.08 (1H,d,J=4.5 Hz), 5.76 (1H,d,d,J=4.5 Hz,8.0 Hz), 6.43(1H,d,J=7 Hz), 7.03 (2H, broad s), 8.10 (1H,d,J=7 Hz), 9.37 (1H,d,J=8.0Hz).

(17)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-carbomoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200°-204° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320,1040, 985, 720 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.38, 3.61 (2H,ABq,J=18 Hz), 3.94 (3H,s), 4.62,4.90 (2H,ABq,J=13 Hz), 5.15 (1H,d,J=4.5 Hz), 5.80 (1H,d,d,J=4.5 Hz, 8.0Hz), 6.44 (1H,d,J=7.0 Hz), 6.58 (2H,s), 7.03 (2H,broad s), 8.10(1H,d,J=7.0 Hz), 9.41 (1H, d,J=8.0 Hz).

(18)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 168°-173° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3240, 1780, 1680-1630 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.33 (3H,s), 3.2, 3.7 (2H, ABq,J=18 Hz), 3.92(3H,s), 3.9-4.2 (2H,m), 5.10 (1H,d,J=4.5 Hz), 5.78 (1H,d,d,J=4.5 Hz,8Hz), 6.40 (1H,d,J=6 Hz), 7.02 (2H,broad s), 8.08 (1H,d,J=6 Hz), 9.37(1H, d,J=8 Hz).

(19) 4-Nitrobenzyl7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate(syn isomer), mp 100°-108° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3210, 1780, 1740, 1680, 1630, 1520, 1375,1350, 1220, 1040, 850, 735 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.75, 4.07 (2H,ABq, J=18 Hz), 3.93 (3H,s), 5.30(1H, d,J=4.5 Hz), 5.45 (2H,s), 5.95 (1H,d,d,J=4.5 Hz,8.0 Hz), 6.42(1H,d,J=7.0 Hz), 7.06 (2H, broad s), 7.68 (2H,d,J=8.0 Hz), 8.22(2H,d,J=8.0 Hz), 8.08 (1H,d,J=7.0 Hz), 9.53 (1H,d,J=8.0 Hz).

(20) Sodium7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate(syn isomer), mp 211°-221° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040,835, 728 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.3∝3.7 (2H,m), 3.90 (3H,s), 4.4 (2H,m), 5.00(1H,d, J=4.5 Hz), 5.6 (1H,m), 6.45 (1H, d,J=7 Hz), 7.05 (2H,broad s),7.5-8.1 (4H,m), 8.10 (1H,d,J=7 Hz), 9.3 (1H,m).

(21)7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 173°-178° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380,1040, 900, 800 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.72 (2H,broad s), 4.00 (3H,s), 4.28, 4.63 (2H,ABq, J=13 Hz), 5.17 (1H,d,J=4.5 Hz), 5.85 (1H,d,d,J=4.5 Hz, 8.0 Hz),6.50 (1H,s), 7.4 (2H,broad s), 9.50 (1H,d,J=8.0 Hz), 9.58 (1H,s).

(22)7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1585 cm⁻¹.

(23)7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3375, 3225, 1780, 1660, 1590, 1540 cm⁻¹.

(24)7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3230, 1780, 1660, 1585, 1540 cm⁻¹.

(25)7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3230, 1780, 1660, 1590, 1540 cm⁻¹.

(26)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1670, 1620, 810, 725 cm⁻¹.

(27)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1665, 1620, 1250, 990, 805cm⁻¹.

(28)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-[1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620 cm⁻¹.

(29)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1778, 1688, 1665, 1623, 1552 cm⁻¹.

(30)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1084,1025 cm⁻¹.

(31)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040,985, 725 cm⁻¹.

(32)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570,1380, 1270, 1095, 1040, 860 cm⁻¹.

(33)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1590 cm⁻¹.

(34)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 1770, 1660, 1530 cm⁻¹.

(35)7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid, mp 161°-163° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1040cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73(2H, broad s), 3.83(3H,s), 3.97(3H,s),4.27,4.63(2H, ABq,J=13 Hz), 5.17(1H,d,J=4.5 Hz), 5.73 (1H,s),5.87(1H,d,d,J=4.5 Hz,8 Hz), 6.77 (2H,broad s), 9.45 (1H,m), 9.57(1H,s).

(36)7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid, mp 148°-160° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3250, 1780, 1680, 1630, 1570, 750, 722cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.7(2H,m), 3,95 (3H,s), 4.28,4.60(2H,ABq,J=13Hz), 5.16 (1H,d,J=4.5 Hz), 5.8(2H,m), 6.98 (2H, broad s), 7.60 (5H,s),9.47(1H,d,J=8 Hz), 9.59 (1H,s).

EXAMPLE 15

(1) A solution of7-[2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (3.97 g) and concentrated hydrochloric acid (0.73 ml)in methenol (80 ml) was stirred for 1.5 hours at ambient temperature.The solvent was evaporated to dryness and the residue was dissolved inwater (100 ml). The aqueous solution was washed with ethyl acetate andadjusted to pH 3 with an aqueous solution of sodium bicarbonate and thensubjected to column chromatography over nonionic adsorption resin,"Diaion HP 20". The column was washed with water and eluted with 50%aqueous methanol. The eluent containing a desired compound wasevaporated to remove themethanol and then lyophilized to give7-[2-(4-aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.75 g), mp 155°-160° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1585 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.27 (3H,t,J=7 Hz), 3.72 (2H, broad s), 4.22(2H,q, J=7 Hz), 4.33, 4.58 (2H,ABq, J=13 Hz), 5.17 (1H,d,J=5 Hz), 5.87(1H,dd,J=5 Hz, and 8 Hz), 6.45 (1H,d,J=6 Hz), 7.03 (2H, broad s), 8.12(1H,d,J=6 Hz), 9.37 (1H,d, J=8 Hz), 9.57 (1H,s).

The following compunds were obtained according to the similar manner tothat of Example 15-(1).

(2)7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 145°-150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3375, 3225, 1780, 1660, 1590, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.90 (3H,t,J=7 Hz), 1.4-1.8 (2H,m), 3.58, 3.74(2H, ABq,J=18 Hz), 4.08 (2H,t,J=7 Hz), 4.26, 4.54 (2H, ABq,J=13 Hz),5.12 (1H,d,J=5 Hz), 5.80(1H,d,d, J=5 Hz,8 Hz), 6.40 (1H,d,J=6 Hz), 7.00(2H,s), 8.06 (1H,d,J=6 Hz), 9.36 (1H,d,J=8 Hz), 9.52 (1H,s).

(3)7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 150°-153° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3230, 1780, 1660, 1585, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.7 (2H,broad s), 4.30, 4.57 (2H,ABq,J=13 Hz),4.68 (2H,d,J=5 Hz), 5.13 (1H,d, J=5 Hz), 5.0-5.6 (2H,m), 5.85(1H,d,d,J=5 Hz,8 Hz), 5.7-6.2(1H,m), 6.42 (1H,d,J=6 Hz), 7.02 (2H, broads), 8.10 (1H,d,J=6 Hz), 9.43 (1H,d,J=8 Hz), 9.57 (1H,s).

(4)7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 145°-150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3370, 3230, 1780, 1660, 1590, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.6 (2H,broad s), 4.33, 4.57 (2H, ABq,J=13 Hz),5.15 (1H, d,J=5 Hz), 5.28 (2H,s), 5.87 (1H, d,d,J=5 Hz,8 Hz), 6.47(1H,d,J=6 Hz), 7.0-7.3 (2H,m), 7.40 (5H,s), 8.13 (1H,d,J=6 Hz), 9.55(1H,d,J=8 Hz), 9.60 (1H,s).

(5)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 148°-153° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1670, 1620, 810, 725 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.8-1.8 (11H,m), 3.73 (2H, broad s), 4.4 (4H,m),5.17 (1H,d,J=4.5 Hz), 5.87 (1H, d,d,J=4.5 Hz,8 Hz), 6.63 (1H,d,J=8 Hz),6.88 (1H,d,J=8 Hz), 7.53 (1H,t,J=8 Hz), 9.45 (1H,d,J=8 Hz).

(6)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 168°-171° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1665, 1620, 1240, 990, 805cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.75 (2H, broad s), 4.20, 4.52 (2H,ABq,J=14 Hz),5.0 (2H,m), 5.06 (1H,d,J=4.6 Hz), 5.3 (2H,m), 5.8-5.9 (2H,m), 6.65(1H,d,J=8 Hz), 6.91 (1H,d,J=8 Hz), 7.50 (1H,t,J=8 Hz), 9.4 (1H,d, J=8Hz).

(7)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 148°-149° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1790, 1670, 1620 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.73 (2H,broad s), 3.93 (3H,s), 4.21, 4.54(2H,ABq,J=14 Hz), 5.0 (2H,m), 5.15 (1H,d,J=4.5 Hz), 5.3 (2H,m), 5.8(1H,m), 5.85 (1H,d,d,J=4.5 Hz,8 Hz), 6.51 (1H,d,J=8 Hz), 6.91 (1H,d,J=8Hz), 7.48 (1H,t,J=8 Hz), 9.5 (1H,d,J=8 Hz).

(8) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 178° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.60,3.74 (2H,ABq, J=19 Hz), 4.22,4.48(2H,ABq,J=14 Hz), 4.68, 4.84 (2H,ABq,J=9 Hz), 5.12 (1H,d,J=5 Hz), 5.30(2H,s), 5.83 (1H,d,d,J=5 Hz,8 Hz), 6.56 (1H,d,J=8 Hz), 6.90 (1H,d,J=8Hz), 7.48 (1H,t,J=8 Hz), 9.66 (1H,d,J=8 Hz).

(9)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)3-cephem-4-carboxylicacid (syn isomer), mp 168°-175° C. (dec.).

I.R. ν_(Max) ^(Nujol) : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085,1025cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.6 (3H,m), 4.30, 4.60 (2H,ABq,J=13 Hz), 500 (2H,s), 5.22 (1H,d,J=4.5 Hz), 5.83 (1H, d,d,J=4.5 Hz, 8.0 Hz), 6.80(1H,d,J=6 Hz), 7.16 (1H,d,J=6 Hz), 7.90 (1H,t,J=6 Hz), 9.60 (1H,s),10.01 (1H,d,J=8 Hz).

(10)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1680-1640cm⁻¹.

(11)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040,985, 725cm⁻¹.

(12) 7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3300, 1780, 1665, 1635, 1590cm⁻¹.

(13) 7-[2-(4-Aminopyrimidin-B 2-yl)-2-methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3210, 1765, 1680-1630, 1580, 1375, 1040,920, 720cm⁻¹.

(14)7-[2-(4-Aminopyimidin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cepyem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320,1040, 985, 720cm⁻¹.

(15)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer)

I.R. ν_(max) ^(Nujol) : 3400, 3240, 1780, 1680-1630cm⁻¹.

(16)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570,1380, 1270, 1095, 1040, 860 cm⁻¹.

(17) Sodium7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate(syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040,835, 728cm⁻¹.

(18)7-[2-(4-Amino-6-chloropyimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380,1040, 900, 800cm⁻¹.

(19)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1590cm⁻¹.

(20)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 1770, 1660, 1530cm⁻¹.

(21)7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1040cm⁻¹.

(22)7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

I.R. ν_(max) ^(Nujol) : 3370, 3250, 1780, 1680, 1630, 1570, 750, 722cm⁻¹.

EXAMPLE 16

A solution of7-[2-allyloxyimino-2-(6-formamidopyridin-2-yl)acetamido]-3-(5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (2.7 g) in formic acid (27 ml) was stirred for 2 hoursat ambient temperature and evaporated to dryness. To the residue wereadded methanol (50 ml) and concentrated hydrochloric acid (0.82 g), andthe mixture was stirred for an hour at ambient temperature. The solventwas evaporated and the residue was dissolved in water (50 ml), adjustedto pH 4 to 5 with an aqueous solution of sodium bicarbonate, treatedwith an activated charcoal and then subjected to column chromatographyover nonionic adsorption resin, "Diaion HP 20" (80 ml). The column waswashed with water and eluted with 50% aqueous methanol. The eluentcontaining a desired compound was evaporated to remove the methanol andthen lyophilized to give7-[2-allyloxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (0.6 g), mp 180° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1770, 1670, 1620cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.63 (2H, broad s), 4.2-4.8 (6H,m), 4.8-6.3(5H,m), 6.53 (1H,d,J=8 Hz), 6.90 (1H,d,J=8 Hz), 7.47 (1H,t,J=8 Hz).

EXAMPLE 17

(1) A mixture of 4-nitrobenzyl7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate(syn isomer) (3.0 g) and 10% palladium on carbon (1.5 g) in 50% aqueoustetrahydrofuran (90 ml) was stirred under hydrogen atmosphere for 3hours at ambient temperature. The catalyst was removed by filtration andthe filtrate was concentrated to half of the original volume. Theremaining aqueous solution was diluted with water (100 ml), washed withethyl acetate, adjusted to pH 3 with 10% hydrochloric acid and subjectedto column chromatography over nonionic adsorption resin, "Diaion HP20".The column was washed with water and eluted with 10% methanol. Theeluent containing a desired compound was evaporated to remove themethanol in vacuo and then lyophilized to give7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (syn isomer) (750 mg), mp 191°-197° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1680-1630, 1585, 1378, 1040,985, 725cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.6 (2H,m), 4.00 (3H, s), 5.13 (1H,d,J=4.5 Hz),5.91 (1H,dd,J=4.5 Hz,8 Hz), 6.50 (1H,d,J=7 Hz), 6.6 (1H,m), 7.03 (2H,broad s), 8.17 (1H,d,J=7 Hz), 9.47 (1H,d,J=8 Hz).

The following compounds were obtained according to the similar manner tothat of Example 17-(1).

(2)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer), mp 200°-205° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3460, 3400, 3260, 1773, 1680-1650, 1620, 1570,1380, 1270, 1095, 1040, 860cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.60, 4.03 (2H,ABq, J=18 Hz), 3.95 (3H,s), 5.25(1H,d,J=4.5 Hz) 5.85 (1H,d,d,J=4.5 Hz, 8.0 Hz), 6.43 (1H,d,J=7 Hz), 7.03(2H, broad s), 8.11 (1H,d,J=7.0 Hz), 9.50 (1H,d,J=8.0 Hz).

(3)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1-allyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1680-1640cm⁻¹.

(4)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3300, 1780, 1665, 1635, 1590cm⁻¹.

(5)7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetaido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3210, 1765, 1680-1630, 1580, 1375, 1040,920, 720cm⁻¹.

(6)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3200, 1775, 1710, 1670-1630, 1400, 1320,1040, 985, 720cm⁻¹.

(7)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-acetylthiomethyl-3-cephem-4-carboxylicacid (syn isomer)

I.R. ν_(max) ^(Nujol) : 3400, 3240, 1780, 1680-1630cm⁻¹.

(8) Sodium7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate(syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040,835, 728cm⁻¹.

(9)7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380,1040, 900, 800cm⁻¹.

(10)7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1585cm⁻¹.

(11)7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3375, 3225, 1780, 1660, 1590, 1540cm⁻¹.

(12) 7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiometyl)-3-cephem-4-carboxylic acid(syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3230, 1780, 1660, 1585, 1540cm⁻¹.

(13)7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3230, 1780, 1660, 1590, 1540cm⁻¹.

(14)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-ceplem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1670, 1620, 810, 725cm⁻¹.

(15)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-4-carboxylic acid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1665, 1620, 1250, 990,805cm⁻¹.

(16)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]3-cephem-B4-carboxylic acid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620cm⁻¹.

(17) 7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm⁻¹.

(18) 7-[2-(6-Aminopyridin-2-yl)-2-propagyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085,1025cm⁻¹.

(19)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1590cm⁻¹.

(20)7-[2-4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 1770, 1660, 1530cm⁻¹.

(21)7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1675, 1620, 1580, 1380,1040cm⁻¹.

(22)7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3370, 3250, 1780, 1680, 1570, 750, 722cm⁻¹.

(23) Benzhydryl7-[2-(6-formamidopyridin-2-yl)2-methoximinoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(1.1 g) was added to a cooled mixture of trifluoroacetic acid (10 ml)and anisole (2 ml), and stirred under ice cooling for 30 minutes. Afterremoving the solvent from the resultant solution, the residue wastriturated with diethyl ether. The precipitates were collected byfiltration and washed with diethyl ether to give7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (900 mg), mp 124° to 128° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400-3200, 1780, 1700, 1670 cm⁻¹.

N.M.R. δppm (aceton-d₆): 3.59 (3H, s), 3.63, 3.76 (2H, AB-q, J=18 Hz),4.00 (6H, s), 4.36 (2H, broad s), 5.13 (1H, s), 6.90-8.10 (3H, m).

EXAMPLE 18

(1) A mixture of7-[2-(2,2,2-trifluoroethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]cephalosporanicacid (4.7 g), disodium salt of 2-(5-mercapto-1H-tetrazol-1-yl)aceticacid (2.3 g) and sodium bicarbonate (0.72 g) in phosphate buffer (pH6.4, 150 ml) was stirred for 3 hours at 60° to 65° C. and then for 2hours with an additional disodium salt of2-(5-mercapto-1H-tetrazol-1-yl) acetic acid (0.88 g) at the sametemperature. The reaction mixture was cooled in an ice bath, adjusted topH 4.5 with 10% hydrochloric acid and washed with ethyl acetate. Theaqueous solution was acidified to pH 1 with 10% hydrochloric acid andextracted with ethyl acetate. The extract was washed with water, driedover anhydrous magnesium sulfate and evaporated to dryness. The residuewas triturated with diethyl ether and washed with the same solvent togive crude 7-[2-(2,2,2-trifluoroethoxyimino)-2-(6-formamidopyridin-2-yl)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer) (2.3 g).

This compound was identified by transforming it to7-[2-(2,2,2-trifluoroethoxyimino)-2-(6-aminopyridin-2-yl)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer) according to the similar manner to that of Example2-(8).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1778, 1688, 1665, 1623, 1552cm⁻¹.

The following compound was obtained according to the similar manner tothat of Example 18-(1).

(2) 7-[2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 170°-175° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1780, 1710, 1680, 1570 cm⁻¹.

N.M.R.δppm (DMSO-d₆): 3.76 (2H,broad, s), 4.00 (3H,s), 4.27, 4.63 (2H,ABq,J=14 Hz), 5.20 (1H,d,J=4 Hz), 5.90 (1H,d,d,J=4 Hz,8 Hz), 7.43 (1H,broad s), 7.77 (1H,d,J=10 Hz), 8.58 (1H,d,J=10 Hz), 8.70 (1H,d,J=4 Hz),9.10 (1H,broad s), 9.55 (1H,d,J=8 Hz).

(3) A mixture of7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) (2.8 g), 2-mercatopyrazine (0.853 g) and sodiumbicarbonate (1.48 g) in phosphate buffer (pH 6.86, 120 ml) was stirredfor 3 hours at 70° C. The reaction mixture was cooled in an ice bath andadjusted to pH 2 with 10% hydrochloric acid. A resultant solid wasfiltered and the filtrate was washed three times with ethyl acetate. Thesolid was dissolved in a mixture of ethyl acetate, acetone and water,and then the aqueous layer was separated out. The filtrate and theaqueous layer were combined, concentrated in vacuo to remove acetone andethyl acetate and, then subjected to column chromatography over nonionicadsorption resin, "Diaion HP 20".

The column was washed with water and 20% aqueous methanol and elutedwith 50% aqueous methanol. The eluent was evaporated to remove themethanol in vacuo and then lyophilized to give7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(pyrazin-2-yl-thiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (0.9 g), mp 175°-180° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1590 cm⁻¹.

N.M.R.δppm (DMSO-d₆): 3.55,3.73(2H,ABq,J=18 Hz), 4.00 (3H,s), 4.10, 4.62(2H,ABq,J=13 Hz) 5.17 (1H,d,J=4 Hz), 5.83 (1H,d,d,J=4 Hz,8 Hz), 6.48(1H,d,J=6 Hz), 7.10 (2H,s), 8.15 (1H,d,J=6 Hz), 8.30-8.67 (3H,m), 9.45(1H,d,J=8 Hz).

The following compounds were obtained according to the similar manner tothat of Example 5-(3).

(4)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1780, 1680-1640 cm⁻¹.

(5) Sodium7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthiomethyl]-3-cephem-4-carboxylate(syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3220, 1765, 1670-1600, 1400, 1090, 1040,835, 728 cm⁻¹.

(6)7-[2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3400, 3280, 1780, 1680, 1630, 1575, 1530, 1380,1040, 900, 800 cm⁻¹.

(7)7-[2-(4-Aminopyrimidin-2-yl)-2-ethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 1780, 1660, 1585 cm⁻¹.

(8)7-[2-(4-Aminopyrimidin-2-yl)-2-propoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3375, 3225, 1780, 1660, 1590, 1540 cm⁻¹.

(9)7-[2-Allyloxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3230, 1780, 1660, 1585, 1540 cm⁻¹.

(10)7-[2-(4-Aminopyrimidin-2-yl)-2-benzyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3370, 3230, 1780, 1660, 1590, 1540 cm⁻¹.

(11)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamido]-3-[(1-hexyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1780, 1670, 1620, 810, 725 cm⁻¹.

(12)7-[2-(6-Aminopyridin-2-yl)-2-hydroxyiminoacetamino]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1775, 1665, 1620, 1250, 990, 805cm⁻¹.

(13)7-[2-(6-Aminopyridin-2-yl)-2-methoxyiminoacetamido]-3-[(1-allyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3380, 3240, 1780, 1670, 1620 cm⁻¹.

(14)7-[2-(6-Aminopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3440, 3320, 1778, 1688, 1665, 1623, 1552 cm⁻¹.

(15)7-[2-(6-Aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3300, 3200, 2160, 1775, 1735, 1670, 1630, 1085,1025 cm⁻¹.

(16)7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 200°-203° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 1770, 1660, 1530 cm⁻¹.

N.M.R.δppm (DMSO-d₆): 3.63, 3.77 (2H,ABq,J=18 Hz), 3.93 (3H,s), 4.23,4.60 (2H,ABq,J=14 Hz), 5.12 (1H,d,J=4 Hz), 5.85 (1H,d,d,J=4 Hz,8 Hz),6.45 (1H,d,J=6 Hz), 7.10 (2H,s), 7.75 (1H,d,J=10 Hz), 8.12 (1H,d,J=6Hz), 8.60 (1H,d,J=10 Hz), 9.43 (1H,d,J=8 Hz).

(17)7-[2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3400, 3250, 1780, 1675, 1620, 1580, 1380, 1040cm⁻¹.

(18)7-[2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid.

I.R. ν_(max) ^(Nujol) : 3370, 3250, 1780, 1680, 1630, 1570, 750, 722cm⁻¹.

EXAMPLE 19

7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was obtained by reacting7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid, which can be prepared from 7-aminocephalosporanic acid and1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazole-5-thiol, with2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) insubstantially the same manner as that of Example 14-(1).

Physical constant of7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid:

mp 185°-189° C. (dec.)

I.R. ν_(max) ^(Nujol) : 3420, 3200, 1810, 1700, 1620, 1525, 1290, 1175cm⁻¹.

N.M.R.δppm (NaHCO₃ +D₂ O): 1.33 (9H, s), 3.3-3.9 (4H, m), 4.20, 4.40(2H, ABq, J=13 Hz), 4.5-4.9 (2H, m), 5.10 (1H, d, J=5 Hz), 5.51 (1H, d,J=5 Hz).

Physical constant of7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer);

I.R. ν_(max) ^(Nujol) : 3400, 3220, 1790, 1720-1640, 1530, 1260, 1175,1055, 725 cm⁻¹.

N.M.R.δppm (DMSO-d₆ +D₂ O): 1.66 (9H, s), 3.0-3.7 (2H, m), 3.7 (2H, m),4.12 (3H, s), 4.4 (4H, m), 5.19 (1H, d, J=5 Hz), 5.86 (1H, d, J=5 Hz),6.90 (1H, d, J=7 Hz), 8.23 (1H, d, J=7 Hz).

EXAMPLE 20

7-[2-(4-Aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was obtained from the object compound in Example 19 insubstantially the same manner as that of Example 3, mp 183°-195° C.(dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3220, 1770, 1660, 1630, 1550, 1540, 1180,1040 cm⁻¹.

N.M.R.δppm (DMSO-d₆ +D₂ O): 3.1-3.8 (4H, m), 3.99 (3H, s), 4.3 (2H, m),4.7 (2H, m), 5.12 (1H, d, J=5 Hz), 5.82 (1H, d, J=5 Hz), 6.61 (1H, d,J=7 Hz), 8.28 (1H, d, J=7 Hz).

EXAMPLE 21

(1) Methylene chloride (15 ml) was added to a Vilsmeier reagent, whichwas prepared by phosphoryl chloride (0.75 g) and N,N-dimethylformamide(0.75 ml) in a conventional manner. To this mixture was added2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer)(1.0 g) at -20° C., followed by stirring at -15° to -13° C. for half anhour. To this solution was added a solution of7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid(1.27 g) and trimethylsilylacetamide (4.6 g) in methylene chloride (14ml) at -20° C. with stirring, and the stirring was continued at -15° to-13° C. for half an hour and at ambient temperature for additional halfan hour. The reaction mixture was evaporated to give a residue, to whichethyl acetate and then an aqueous solution of sodium bicarbonate wereadded. To the separated aqueous solution was added ethyl acetate andthen adjusted to pH 1 to 2 with hydrochloric acid.

After addition of a small amount of acetone, the organic layer wasseparated, washed with water and an aqueous solution of sodium chloride,dried over magnesium sulfate, and then evaporated. The residue waspulverized with diethyl ether to give7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.45 g).

I.R. ν_(max) ^(Nujol) : 1780, 1710, 1660, 1570, 1210, 1060, 1000, 760cm⁻¹.

N.M.R. δppm (DMSO-d6): 3.73 (2H, m), 4.27, 4.67 (2H, ABq, J=12 Hz), 5.27(1H, d, J=5 Hz), 5.97 (1H, dd, J=5 Hz, 8 Hz), 6.9-7.6 (5H, m), 7.7-8.2(1H, m), 8.77 (1H, d, J=6 Hz), 9.10 (1H, m), 9.54 (1H, s), 9.83 (1H, d,J=8 Hz), 11.10 (1H, d, J=7 Hz).

(2)7-[2-(4-Formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (syn isomer) (1.8 g) was obtained by reacting7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (2.12 g) with an activated acid prepared from2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer)(1.1 g), phosphoryl chloride (0.83 g) and N,N-dimethylformamide (0.8ml), in substantially the same manner as that of Example 21-(1).

I.R. ν_(max) ^(Nujol) : 3300-3100, 1770, 1715-1660, 1570, 1250, 1210,1160, 990, 850, 760 cm⁻¹.

N.M.R. δppm (DMSO-d6): 1.25 (9H, s), 3.23 (2H, m), 3.70 (2H, m), 4.27(4H, m), 5.17 (1H, d, J=5 Hz), 5.90 (1H, m), 6.8-7.6 (5H, m), 7.90 (1H,m), 8.73 (1H, d, J=6 Hz), 9.83 (1H, d, J=8 Hz), 11.20 (1H, d, J=7 Hz).

EXAMPLE 22

(1) A solution of7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer) (1.40 g) and coc. hydrochloric acid (0.23 ml) inmethanol (20 ml) was stirred at ambient temperature for 1.5 hours.

The reaction mixture was poured into diethyl ether (150 ml) withstirring, followed by the precipitates were collected by filtration,washed with diethyl ether and dried to give a pale yellow powder (1.2g). To this powder was added water (6 ml) and the suspension was stirredfor 20 minutes. The remaining powder was collected by filtration, washedwith water and then dried in vaccuo to give a pale yellow powder (0.96g) of hydrochloric acid salt of7-[2-(4-aminopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid (syn isomer), mp 155°-161° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 3160, 1770, 1650, 1580, 1200, 1060, 1000,980, 760 cm⁻¹.

N.M.R.δppm (DMSO-d6+D₂ O): 3.76 (2H, m), 4.11, 4.64 (2H, ABq, J=13 Hz),5.28 (1H, d, J=5 Hz), 5.95 (1H, d, J=5 Hz), 6.73 (1H, d, J=6 Hz),7.0-7.6 (5H, m), 8.30 (1H, d, J=6 Hz), 9.63 (1H, s).

(2) A solution of formic acid salt of7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (syn isomer) (1.5 g) and conc. hydrochloric acid (0.45 ml) inmethanol (20 ml) was stirred at ambient temperature for 1.5 hours. Thereaction mixture was concentrated till the precipitates appearedtherein, and to the concentrate was added water (double volume of saidconcentrate).

The aqueous solution was chromatographed on non-ionic adsorption resin"Diaion HP-20" (Trade Mark: maker Mitsubishi Chemical Industries Ltd.)(60 ml) with 20% aqueous methanol (500 ml), 30% aqueous methanol (300ml) and then 60% aqueous methanol (500 ml) as an eluent, and thefractions containing a desired compound were collected. These fractionswere concentrated to a volume of 150 ml and the concentrate waslyophilized to give a pale yellow powder (0.55 g) of7-[2-(4-aminopyrimidin-2-yl)-2-phenoxy-iminoacetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (syn isomer), mp 217°-227° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 3160, 1760, 1660, 1620, 1580, 1200, 980,950, 760 cm⁻¹.

N.M.R.δppm (DMSO-d6+D₂ O): 3.1-3.8 (4H, m), 4.27 (2H, m), 4.69 (2H, m),5.17 (1H, d, J=5 Hz), 5.87 (1H, d, J=5 Hz), 6.60 (1H, d, J=6 Hz),7.0-7.7 (5H, m), 8.27 (1H, d, J=6 Hz).

EXAMPLE 23

To7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (syn isomer) (1.7 g) was added formic acid (17 ml) and the solutionwas stirred at ambient temperature for 4 hours. After the reactionmixture was evaporated, the residue was pulverized with ethyl acetate togive a brown powder (1.5 g) of formic acid salt of7-[2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetamido]3-[1-(2-aminoethyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylicacid (syn isomer).

I.R. ν_(max) ^(Nujol) : 3200, 1770, 1710, 1660, 1570, 1210, 990, 760cm⁻¹.

PREPARATION OF THE STARTING COMPOUNDS Preparation 1

(1) A 15% n-hexane solution (636 g.) of n-butyllithium was added to asolution of 6-amino-2-methylpyridine (64.8 g.) in tetrahydrofuran (500ml.) at -20° to -30° C. over one hour, and stirred at -8° to -10° C. for30 minutes. To the solution was added trimethylsilylchloride (161.7 g.)at -15° to -5° C. over 40 minutes, and the resultant solution wasstirred at room temperature overnight. The solution was filtered throughby a column packed with silica gel (180 g.), washed with tetrahydrofuranand then the filtrate was concentrated under reduced pressure. Theresidue was purified by fractional distillation to give6-[N,N-bis(trimethylsilyl)amino-2-methylpyridine (117.6 g.), b.p. 95° to97° C./5-6 mm.

N.M.R. δppm (CCl₄): 0.13 (18H, s), 2.35 (3H, s), 6.43 (1H, d, J=8 Hz),6.60 (1H, d, J=8 Hz), 7.25 (1H, t, J=8 Hz).

(2) A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwiseadded to a solution of 6-[N,N-bis(trimethylsilyl)amino]-2-methylpyridine(100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20° to -30° C. overone hour and the solution was stirred at 20° to 23° C. for one hour. Theresultant solution was added in small portions to crushed dry ice (1kg.) under stirring, and stirred till a room temperature. After removingtetrahydrofuran from the solution under reduced pressure, absoluteethanol (1 l) was added to the residue. 30% Ethanol solution (660 ml.)of hydrochloric acid was dropwise added to the solution at -5° to -10°C., and further hydrogen chloride gas was bubbled at 0° to 5° C. for 30minutes and then the solution was stirred at 10° C. overnight. Afterremoving ethanol from the resultant solution, the residue was dissolvedin water, and washed with ethyl acetate 3 times. The solution wasadjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethylacetate. The ethyl acetate extract was washed with a saturated aqueoussolution of sodium chloride, dried and concentrated under reducedpressure to give the crude product (54 g.) The product was purified bycolumn chromatography on silica gel (1 kg.) with an eluent (ethylacetate+benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.),mp 66° to 68° C.

I.R. ν_(max) ^(Nujol) : 3430, 3340, 3200, 1730, 1645, 1480, 1190 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.25 (3H, t, J=6 Hz), 3.67 (2H, s), 4.20 (2H, q,J=6 Hz), 5.33 (2H, broad s), 6.43 (1H, d, J=8 Hz), 6.62 (1H, d, J=8 Hz),7.40 (1H, t, J=8 Hz).

(3) Acetic anhydride (16.6 ml.) and 98% formic acid (7.32 ml.) weremixed at room temperature and stirred at 50° to 66° C. for 30 minutes.The solution was dropwise added to a solution of ethyl2-(6-aminopyridin-2-yl)acetate (26.5 g.) in ethyl acetate (250 ml.) at20° to 23° C. over 30 minutes, and stirred at the same temperature forone hour. Cool water was added to the resultant solution and shakedsufficiently. The ethyl acetate layer was separated, washed with water,an aqueous solution of sodium bicarbonate and water in turn, dried andconcentrated under reduced pressure to give ethyl2-(6-formamidopyridin-2-yl)acetate (28 g.), mp 35° to 38° C.

I.R. ν_(max) ^(Nujol) : 3250, 3100, 1738, 1690, 1580, 1460, 1305, 1277cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.17 (3H, t, J=8 Hz), 3.75 (2H, s), 4.08 (2H, q,J=8 Hz), 6.85 (0.5 H, broad d, J=8 Hz), 7.95 (0.5H, broad s), 7.08 (1H,d, J=8 Hz), 7.73 (1H, t, J=8 Hz), 8.33 (0.5 H, broad s), 9.25 (0.5 H,broad d), 10.58 (1H, broad s).

(4) To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) indioxane (260 ml.) was added selenium dioxide (16.65 g.) in smallportions at 85° to 90° C. over one hour and stirred at the sametemperature for one hour. After cooling the resultant solution thedioxane layer was separated and concentrated under reduced pressure andthen the residue was dissolved in ethyl acetate. The solution was washedwith water, dried over magnesium sulfate and treated with activatedchrcoal and then concentrated under reduced pressure. The residue wastriturated with diethyl ether to give ethyl2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp 124° to 126° C.

I.R. ν_(max) ^(Nujol) : 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.34 (3H, t, J=8 Hz), 4.44 (2H, q, J=8 Hz), 7.33(0.65H, broad s), 7.8-8.2 (0.35H), 7.84 (1H, d, J=8 Hz), 8.09 (1H, t,J=8 Hz), 8.44 (0.35H, broad s), 9.22 (0.65H, broad s), 10.85 (1H, broads).

(5) 2 N Sodium hydroxide solution [solvent:water (1 part)+ethanol (4parts)] (14.87 ml.) was added to a solution of ethyl2-(6-formamidopyridin-2-yl)glyoxylate (6.00 g.) in ethanol (180 ml.) atroom temperature and stirred at the same temperature for 20 minutes.Methoxyamine hydrochloride (2.71 g.) was added to the resultantsolution, stirred at room temperature for 1.5 hours and thenconcentrated to a small volume under reduced pressure. The precipitateswere collected by filteration washed with ethyl acetate and water,dissolved in methanol and then treated with activated charcoal. Thesolution was concentrated under reduced pressure and then theprecipitates were collected by filtration to give2-(6-formamidopyridin-2-yl)-2-methoxylminoacetic acid (3.63 g.), mp 170°to 171° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3230, 3132, 1745, 1680, 1575, 1450, 1320, 1208,1032 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (3H, s), 6.90 (0.6H, broad d), 7.9 (0.4H,broad s), 7.10 (1H, d, J=8 Hz), 7.75 (1H, t, J=8 Hz), 8.38 (0.4H, broads), 9.25 (0.6H, broad d), 10.58 (1H, broad d).

(6) To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g.)in ethanol (44 ml.) was added 2 N sodium hydroxide solution[solvent:water (1 part)+ethanol (4 parts] (15.9 ml.) at 18° to 20° C.over 30 minutes, and then the solution was stirred at room temperaturefor one hour. After 1 N hydrochloric acid (31.7 ml.) was added to thesolution, the solution was concentrated under reduced pressure. Theresidue was extracted with hot ethyl acetate (500 ml.) and the extractwas concentrated under reduced pressure. The residue was washed withethyl acetate to give 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g.),mp 125° to 126° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3270, 1720, 1655, 1575, 1460 cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.70 (2H, s), 6.9 and 7.9 (1H, m), 7.10(1H, d, J=8 Hz), 7.75 (1H, t, J=8 Hz), 9.25 and 8.38 (1H, broad s).

(7) A suspension of 2(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid(1.5 g.) and conc. hydrochloric acid (0.77 g.) in methanol (30 ml.) wasstirred at room temperature for 45 minutes. After concentrating theresultant solution under reduced pressure, the residue was washed withdiethyl ether. The precipitates were collected by filtration to give2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (1.63g.), mp 100° to 105° C.

I.R. ν_(max) ^(Nujol) : 3400-3150, 1730, 1670, 1245, 1050, 803 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.13 (3H, s), 6.89 (1H, d, J=8 Hz), 7.22 (1H, d,J=8.5 Hz), 7.95 (1H, dd, J=8.5 Hz, 8 Hz).

(8) Bis(trimethylsilyl)acetamide (1.61 g.) was added to a stirredsuspension of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acidhydrochloride (410 mg.) in ethyl acetate (5 ml.) all at once, andstirred at 40° C. for 50 minutes. Trifluoroacetic anhydride (1.3 g.) wasdropped into the solution at -10° to -5° C. over 30 minutes, and thenthe solution was stirred at the same temperature for 3 hours. Ethylacetate (10 ml.) and water (3 ml.) were added to the resultant solution.The solution was washed with water and a saturated aqueous solution ofsodium bicarbonate in turn, dried over magnesium sulfate, andconcentrated under reduced pressure to give2-(6-trifluoroacetamidopyridin-2-yl)-2-methoxyiminoacetic acid (470mg.), mp 194° to 195° C.

I.R. ν_(max) ^(Nujol) : 3350, 1680-1670, 1600, 1380, 1040, 850, 810cm⁻¹.

(9) 1 N Sodium hydroxide (27.5 ml.) was added to a stirred solution ofethyl 2-(6-formamidopyridin-2-yl)glyoxylate (5.55 g.) in ethanol (100ml.) at room temperature, and the solution was stirred at the sametemperature for 30 minutes. To the solution was added hydroxylaminehydrochloride (1.9 g.) all at once, and the solution was stirred at roomtemperature for 2 hours. After removing ethanol from the resultantsolution under reduced pressure, ethylacetate was added to the residue,and then the solution was adjusted to pH 7 with an aqueous solution ofsodium bicarbonate. The aqueous layer was separated and adjusted to pH 2with 10% hydrochloric acid. The precipitates were collected byfiltration, washed with water and dried to give2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid (3.6 g.), mp 190°to 192° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3120, 1700, 1665, 1620 cm⁻¹.

(10) A mixture of 2-(6-formamidopyridin-2-yl)-2-hydroxyiminoacetic acid(3.6 g.), dichloroacetyl chloride (7.6 g.) and methylene chloride (100ml.) was stirred at room temperature for 5 hours. The precipitates werecollected by filtration, washed with diethyl ether and dried to give2-(6-formamidopyridin-2-yl)-2-dichloroacetoxyiminoacetic acid (4.6 g.),mp 88° to 90° C.

I.R. ν_(max) ^(Nujol) : 1800, 1720, 1620 cm⁻¹.

Preparation 2

(1) A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.)was stirred at 50° to 60° C. for 30 minutes. The solution was added to asuspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) inethyl acetate (300 ml.) at room temperature over 10 minutes, and thesolution was stirred at room temperature for 3 hours. After removing theinsoluble substance by filtration, water (300 ml.) was added to thefiltrate, and then the mixture was adjusted to pH 7 with sodiumbicarbonate. The aqueous layer was separated and extracted with ethylacetate. The extract and the organic layer were combined, washed with asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate, treated with activated charcoal, and then concentrated underreduced pressure. The residue was triturated with diethyl ether to givemethyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103° to 107°C.

I.R. ν_(max) ^(Nujol) : 3000-3400 (multiple), 1740, 1703, 1600, 1567cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (3H, s), 3.90 (2H, s), 7.25 (1H, d, J=5 Hz),8.60 (1H, d, J=5 Hz), 9.43 (1H, d, J=10 Hz), 11.07 (1H, broad d, J=10Hz).

(2) Selenium oxide (9.92 g.) was added to a solution of methyl2-(2-formamidopyrimidin-4-yl)acetate (14.52 g.) in dioxane (200 ml.) at90° to 95° C. over 20 minutes, and stirred at the same temperature foran hour. After cooling the resultant solution, the solution was filteredthrough a column packed with silica gel (20 g.), washed with dioxane andconcentrated under reduced pressure. The residue was dissolved inacetone and filtered, and then the filtrate was concentrated underreduced pressure. The residue was triturated with chloroform to give acrude product (8.2 g.). The product was added to ethyl acetate, heatedand an insoluble material was filtered out. The filtrate was cooled, andthe precipitates were collected by filtration to give methyl2-(2-formamidopyrimidin-4-yl)glyoxylate (5.55 g.). The product wasrecrystallized from ethyl acetate (saturated with water) to give monohydrate thereof, mp 143° to 144° C.

Anal. Calcd. for C₈ H₇ N₃ O₄.H₂ O:

    ______________________________________                                                C           H      N                                                  ______________________________________                                        Calcd.    42.30         3.99   18.50                                          found     42.22         3.95   18.34                                          ______________________________________                                    

I.R. ν_(max) ^(Nujol) : 3270, 3200, 1750, 1710, 1597, 1585, 1416, 1233cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.65 (3H, s), 7.30 (2H, s), 7.40 (1H, d, J=5 Hz),8.63 (1H, d, J=5 Hz), 9.33 (1H, d, J=10 Hz), 10.95 (1H, bd, J=10 Hz).

(3) 4 N sodium hydroxide (10.85 ml.) was added to a solution of methyl2-(2-formamidopyrimidin-4-yl)glyoxylate mono hydrate (4.55 g.) inmethanol (60 ml.), and the solution was stirred for an hour.

To the solution was added methoxylamine hydrochloride (1.82 g.) littleby little, and the solution was stirred at room temperature for 30minutes, and then under ice cooling for 30 minutes. The precipitateswere collected by filtration, and dissolved in water. The insolublesubstance was filtered out. The filtrate was adjusted to pH 1 with 10%hydrochloric acid and extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of sodium chloride, andconcentrated under reduced pressure. The precipitates were collected byfiltration to give 2-(2-formamidopyrimidin-4-yl)-2-methoxyiminoaceticacid (0.63 g.). The methanol solution obtained above was concentratedunder reduced pressure, and the residue was dissolved in water. Theaqueous solution was treated with activated charcoal, adjusted to pH 1with 10% hydrochloric acid and extracted with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium chloride andconcentrated under reduced pressure. The precipitates were collected byfiltration to give the same object compound (0.73 g.), total yield 1.36g, mp 180° to 182° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300-2400 (multiple), 1750, 1670, 1590, 1573,1408, 1240, 1048 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.00 (3H, s), 7.47 (1H, d, J=5 Hz), 8.60 (1H, d,J=5 Hz), 9.23 (1H, d, J=10 Hz), 11.02 (1H, broad d, J=10 Hz).

Preparation 3

(1) 1 N Sodium hydroxide solution (8.5 ml.) was added to a stirredsolution of ethyl 2-(6-formamidopyridin-2-yl)-glyoxylate (1.9 g.) inethanol (30 ml.) at room temperature and stirred at the same temperaturefor 30 minutes. After adding ethoxylamine hydrochloride (912 mg.) to thesolution, the solution was stirred at room temperature for 4 hours. Theresultant solution was concentrated under reduced pressure, and ethylacetate and an aqueous solution of sodium bicarbonate were added to theresidue. The aqueous layer was separated and ethyl acetate was added tothe solution. The solution was adjusted to pH 1 with 10% hydrochloricacid. The ethyl acetate layer was separated, dried over magnesiumsulfate and concentrated under reduced pressure. The residue wastriturated with a mixture of diethyl ether and petroleum ether to give2-(6-formamidopyridin-2-yl)-2-ethoxyiminoacetic acid (920 mg.), mp. 155°to 156° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1740, 1650 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.3 (3H, t, J=7 Hz), 4.3 (2H, q, J=7 Hz), 6.8-8.2(3H, m), 9.4 (1H, broad d), 10.5 (1H, broad d).

Preparation 4

(1) A mixture of formic acid (20 g.) and acetic anhydride (41.3 g.) wasstirred for 30 minutes at 50° C. and thereto was added methyl4-amino-2-pyridinecarboxylate (11 g.) at ambient temperature, and thenthe mixture was stirred for 2 hours at 70°-75° C. After the removal ofthe solvent from the reaction mixture, the residue was recrystallizedfrom ethanol (160 ml.) to give a pale yellow powder of methyl4-formamido-2-pyridinecarboxylate (8.3 g.), mp. 185° to 186.5° C.

I.R. ν_(max) ^(Nujol) : 3200-3300, 1690, 1675, 1585, 1570, 1495, 1420,1260, 990, 860, 840 cm⁻¹.

(2) To a mixture of methyl 4-formamido-2-pyridinecarboxylate (9.9 g.),methyl methylthiomethyl sulfoxide (6.82 g.) and N,N-dimethylformamide(200 ml.) was added 50% sodium hydride (7.92 g.) with stirring at 10° C.and the stirring was continued for further 10.5 hours at 45° C. Afterthe removal of N,N-dimethylformamide from the reaction mixture, to theresidue was added a cold mixture of ethyl acetate and dilutedhydrochloric acid. The ethyl acetate layer was separated and theremaining aqueous layer was further extracted with ethyl acetate. Thecombined extract was washed with an aqueous solution of sodium chloride,dried over magnesium sulfate and the solvent was distilled off. Theresidue (6.0 g.) was washed with a mixture of ethyl acetate and diethylether, collected by filtration and then dried to give the brownishyellow powder of4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (1.96 g.),mp. 132° to 132.5° C. After the concentration of the filtrate, theprecipitates were collected by filtration, washed with diethyl ether andthen dried to give the same compound (1.11 g.). Total yield: 3.07 g.

I.R. ν_(max) ^(Nujol) : 3200-3225, 1680, 1580, 1290, 1170, 1020, 845cm⁻¹.

(3) After stirring a mixture of acetic anhydride (14 ml.) and formicacid (136 ml.) for 10 minutes at 40° to 50° C.,4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (3.7 g.)was added thereto, and then the stirring was continued at 65° C. for 30minutes. To the mixture was added sodium periodate (0.872 g.), and themixture was stirred for 15 minutes. After the removal of the solventfrom the reaction mixture, the residue was dissolved in ethyl acetate.The solution was washed with an aqueous solution of sodium bicarbonate,aqueous sodium thiosulfate and water successively, and then dried overanhydrous magnesium sulfate. The solvent was distilled off and theresidue was washed with diethyl ether, collected by filtration and thendried to give a pale yellow powder of S-methyl2-(4-formamidopyridin-2-yl)thioglyoxylate (1.96 g.), mp. 145° to 148° C.

I.R. ν_(max) ^(Nujol) : 3150-3300, 1690, 1670, 1585, 1570, 1500, 1420,1265, 990, 860, 835, 745 cm⁻¹.

(4) A mixture of S-methyl 2-(4-formamidopyridin-2-yl)thioglyoxylate(1.07 g.), methanol (20 ml.) and 1 N aqueous solution of sodiumhydroxide (5.7 ml.) was stirred for 50 minutes at ambient temperature togive a solutions containing 2-(4-formamidopyridin-2-yl)glyoxylic acid.To the solution was added O-methylhydroxylamine hydrochloride (438 mg.),and the mixture was stirred for an hour at ambient temperature. Afterthe removal of the solvent from the reaction mixture, to the residue wasadded water (5 ml.), and the mixture was washed with ethyl acetate andthen water was distilled off. The remaining water in the residue wasazeotropically removed with ethanol and benzene in turn to give a palebrown powder of 2-(4-formamidopyridin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (960 mg.).

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6 + D.sub.2 O):                                                   3.93 (3H, s),                                                                 7.6 (1H, broad)                                                               8.1 (broad s)                                                                                    (1H)                                                       8.55 (broad s)                                                                8.45 (1H, broad s)                                         ______________________________________                                    

Preparation 5

(1) A mixture of formic acid (559.3 g.) and acetic anhydride (1033.4 g.)was stirred for 30 minutes at 40° to 50° C. and thereto was added methyl6-amino-2-pyridinecarboxylate (616 g.) at 40° C., and then the mixturewas stirred for 1 hour at 80° C. After the removal of the solvent fromthe reaction mixture, the residue was dissolved in a mixture of benzeneand n-hexane and then filtered. Thus obtained precipitates wererecrystallized from benzene (2 l.) to give methyl6-formamido-2-pyridinecarboxylate (647.8 g.), mp. 134° to 136° C.

Element analysis:

    ______________________________________                                                 C           N      H                                                 ______________________________________                                        Calcd (%)  53.33         4.48   15.55                                         Found (%)  53.37         4.40   15.58                                         ______________________________________                                    

I.R. ν_(max) ^(Nujol) : 3200, 1740, 1700 cm⁻¹.

(2) To a mixture of methyl 6-formamido-2-pyridinecarboxylate (435.7 g.),methyl methylthiomethyl sulfoxide (300 g.) and N,N-dimethylformamide(2.2 l.) was added 50% sodium hydride (348 g.) with stirring underice-cooling, and the mixture was stirred for 30 minutes at ambienttemperature. To the reaction mixture was added benzene (4.4 l.) underice-cooling and the precipitates were collected by filtration. Theprecipitates were added to a mixture of methylene chloride (3 l.), ice(2 kg.) and concentrated hydrochloric acid (730 ml.). The mixture wasadjusted to pH 7 with sodium bicarbonate and then extracted withmethylene chloride. The extract was dried over magnesium sulfate and thesolvent was distilled off. The residue was crystallized in diethylether, collected by filtration and then dried to give6-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (430 g.),mp. 130° to 132° C.

I.R. ν_(max) ^(Nujol) : 3250, 3150, 3050, 1710, 1690, 1600, 1510 cm⁻¹.

N.M.R. δppm (d₆ -acetone+D₂ O): 2.30 (3H, s), 2.88 (3H, s), 6.00 (1H,s), 7.7-8.2 (3H, m).

(3) A mixture of6-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyridine (424 g.),sodium periodate (100 g.) in acetic acid (2.1 l.) was stirred for 30minutes at 70° C. After the removal of the solvent from the reactionmixture, to the residue were added water (5 l.) and sodium thiosulfate(116 g.), and then the mixture was adjusted to pH 7 with sodiumbicarbonate. The precipitates were collected by filtration, washed withwater and then dried to give S-methyl2-(6-formamidopyridin-2-yl)thioglyoxylate (246.4 g.), mp. 163° to 165°C. Further, the same compound (12 g.) was obtained from the aqueouslayer by extraction with ethyl acetate.

I.R. ν_(max) ^(Nujol) : 3250, 3150, 3080, 1700, 1670, 1595, 1580, 1510cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 2.57 (3H, s), 7.77-8.27 (3H, m).

(4)-(a) A mixture of S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate(4.48 g.), methanol (20 ml.) and 1 N aqueous solution of sodiumhydroxide (20 ml.) was stirred for 50 minutes at ambient temperature togive a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid. Tothe solution was added O-propylhydroxylamine hydrochloride (2.23 g.),and the mixture was stirred for 35 minutes at the same temperature. Thereaction mixture was adjusted to pH 7 with hydrochloric acid and themethanol was distilled off. The remaining aqueous mixture was washedwith ethyl acetate, and ethyl acetate was added thereto and thenadjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer wasseparated, washed with water, dried over magnesium sulfate, treated withactivated charcoal and then the solvent was distilled off. Thus obtainedproduct was washed with a mixture of diethyl ether and diisopropyl etherand then dried to give 2-(6-formamidopyridin-2-yl)-2-propoxyiminoaceticacid (syn isomer) (1.76 g.), mp. 140° to 142° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 3100, 2600, 1755, 1670, 1620, 1580 cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 0.96 (3H, t, J=7 Hz), 1.56-1.84 (2H, m),4.2 (2H, t, J=7 Hz), 7.0-8.32 (3H, m).

Similarly, the following compounds were obtained.

(4)-(b) 2-(6-Formamidopyridin-2-yl)-2-(2,2,2-trifluoroethoxyimino)aceticacid (syn isomer), mp. 183° to 184° C. (dec.)

I.R. ν_(max) ^(Nujol) : 3220, 1760, 1680 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.78, 5.07 (2H, ABq, J=9 Hz), 7.0-8.2 (3H, m),9.0-9.3 (1H, m), 10.76 (1H, m).

(4)-(c) 2-(6-Formamidopyridin-2-yl)-2-isopropoxyiminoacetic acid (synisomer), mp. 140° to 150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 2600, 1750, 1670, 1620, 1580, 1510 cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 1.3 (6H, d, J=6 Hz), 4.36-4.64 (1H, m),6.92-8.28 (3H, m).

(4)-(d) 2-Allyloxyimino-2-(6-formamidopyridin-2-yl)acetic acid (synisomer), mp. 140° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 3100, 2600, 1760, 1670, 1620, 1580 cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 4.67-4.9 (2H, m), 5.17-5.6 (2H, m),5.8-6.52 (1H, m), 7.0-8.33 (3H, m).

(4)-(e) 2-(6-Formamidopyridin-2-yl)-2-propargyloxyiminoacetic acid (synisomer), mp. 145° to 150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3350, 3250, 3100, 2600, 1755, 1685, 1620, 1580,1510 cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 3.04 (1H, t, J=2 Hz), 4.88 (2H, d, J=2Hz), 7.0-8.28 (3H, m).

(4)-(f) 2-Butoxyimino-2-(6-formamidopyridin-2-yl)acetic acid (synisomer), mp. 129° to 131° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3150, 1755, 1670 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 0.7-1.9 (7H, m), 4.20 (2H, t, J=6 Hz), 7.0-8.1(3H, m), 10.7 (1H, broad d).

(4)-(g) 2-Isobutoxyimino-2-(6-formamidopyridin-2-yl)acetic acid (synisomer), mp. 153° to 155° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 3150, 1750, 1680, 1620, 1580 cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 0.96 (6H, d, J=6 Hz), 1.88-2.16 (1H, m),4.0 (2H, d, J=6 Hz), 7.0-8.28 (3H, m).

(4)-(h) 2-(6-Formamidopyridin-2-yl)-2-phenoxyiminoacetic acid (synisomer), mp. 148° to 150° C. (dec.).

I.R. ν_(max) ^(Nujol) : 1730, 1660, 1560 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 6.80-8.2 (8H, m), 10.80 (1H, d, J=8 Hz).

Preparation 6

(1) Methyl 6-formamido-3-pyridinecarboxylate, mp. 218° to 220° C. wasobtained according to the similar manner to that of the Preparation4-(1).

I.R. ν_(max) ^(Nujol) : 3100, 3020, 1710, 1605, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.84 (3H, s), 8.12-8.84 (3H, m).

(2) 2-Formamido-5-(2-methanesulfinyl-2-methylthioacetyl)pyridine, mp.125° to 127° C. was obtained according to the similar manner to that ofPreparation 4-(2).

I.R. ν_(max) ^(Nujol) : 3200, 1710, 1660, 1600, 1545 cm⁻¹.

(3) S-Methyl 2-(6-formamidopyridin-3-yl)thioglyoxylate, mp. 152° to 154°C. was obtained according to the similar manner to that of thePreparation 4-(3) by using acetic acid instead of acetic anhydride andformic acid.

I.R. ν_(max) ^(Nujol) : 3250, 3150, 3050, 1730, 1680, 1600, 1590, 1510cm⁻¹.

N.M.R. δppm (acetone-d₆ +D₂ O): 2.47 (3H, s), 8.35-9.17 (3H, m).

(4) A mixture of S-methyl 2-(6-formamidopyridin-3-yl)thioglyoxylate (13g.), methanol (50 ml.), 1 N aqueous solution of sodium hydroxide (58ml.) and water (150 ml.) was stirred at ambient temperature for 30minutes. To the mixture was added O-methylhydroxylamine hydrochloride(4.85 g.) and then stirred for an hour. The reaction mixture wasadjusted to pH 7 with an aqueous solution of sodium bicarbonate, and themethanol was removed by distillation under reduced pressure. Theremaining aqueous solution was washed with ethyl acetate and thereto wasadded ethyl acetate. The resultant mixture was adjusted to pH 2 with 10%hydrochloric acid and thereto was added sodium chloride, and the mixturewas stirred for a while. The precipitates were collected by filtrationwashed with diisopropyl ether and then dried to give2-(2-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.0g.), mp. 159° to 161° C. (dec.).

I.R. ν_(max) ^(Nujol) : 1735, 1665, 1590, 1550 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.00 (3H, s), 7.8-8.5 (3H, m), 10.87 (1H, d, J=6Hz).

On the other hand, the ethyl acetate layer was separated from thefiltrate and the remaining aqueous layer was further extracted withethyl acetate. The ethyl acetate layers were combined together, driedover magnesium sulfate and then the solvent was distilled off to givepowder of 2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (amixture of syn and anti isomers). Thus obtained powder was dissolved inan aqueous solution of sodium bicarbonate and then adjusted to pH 2 to 3with 10% hydrochloric acid. The precipitates were collected byfiltration and then dried to give2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (anti isomer)(1.45 g.), mp. 168° to 170° C. (dec.).

I.R. ν_(max) ^(Nujol) : 1705, 1605, 1535 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.00 (3H, s), 7.8-8.5 (3H, m), 10.80 (1H, d, J=7Hz).

Further, the mother liquor was adjusted to pH 3 to 4 with an aqueoussolution of sodium bicarbonate. The resultant solution was washed withethyl acetate, adjusted to pH 2 with 10% hydrochloric acid and thenextracted with ethyl acetate. The extract was dried over magnesiumsulfate and then the solvent was distilled off to give further2-(6-formamidopyridin-3-yl)-2-methoxyiminoacetic acid (syn isomer) (2.5g.).

Preparation 7

(1) Methyl 2-formamido-4-pyridine mp. 196° to 197° C. was obtainedaccording to the similar manner to that of the Preparation 4-(1).

I.R. ν_(max) ^(Nujol) : 3100, 1740, 1710, 1580, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.92 (3H, s), 7.48-8.6 (3H, m).

(2)2-Formamido-4-(2-methanesulfinyl-2-methylthioacetyl)pyridine, mp.123° to 125° C. was obtained according to the similar manner to that ofthe Preparation 4-(2).

I.R. ν_(max) ^(Nujol) : 3150, 3050, 1690, 1610, 1565 cm⁻¹.

(3) S-Methyl 2-(2-formamidopyridin-4-yl)thioglyoxylate, mp. 165° to 167°C. was obtained according to the similar manner to that of thePreparation 4-(3) by using acetic acid instead of acetic anhydride andformic acid.

I.R. ν_(max) ^(Nujol) : 3250, 3100, 1710, 1680, 1610, 1565, 1520 cm⁻¹.

N.M.R. δppm (CDCl₃ +D₂ O): 2.48 (3H, s), 7.5-8.6 (3H, m).

(4) 2-(2-Formamidopyridin-4-yl)-2-methoxyiminoacetic acid (syn isomer),mp. 170° to 172° C. (dec.) was obtained according to the similar mannerto that of the Preparation 4-(4) via2-(2-formamidopyridin-4-yl)glyoxylic acid.

I.R. ν_(max) ^(Nujol) : 2500, 1710, 1640, 1615, 1600, 1520 cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 4.02 (3H, s), 7.0-8.6 (3H, m).

Preparation 8

(1) A mixture of ethyl 2-(4-amino-6-hydroxypyrimidin-2-yl)acetate (15.8g.) and phosphoryl chloride (75 ml.) was stirred for 4 hours underheating at 80° to 90° C. The resultant solution was allowed to cool andphosphoryl chloride was distilled off. The remaining oily substance waspoured into a mixture of ice-water (200 ml.) and ethyl acetate (200ml.). The resultant mixture was neutralized with an aqueous solution ofammonia and extracted with ethyl acetate. The extract was washed withwater, dried over magnesium sulfate and then the solvent was distilledoff. The resultant residue was washed with diisopropyl ether and thendried to give pale brown crystals of ethyl2-(4-amino-6-chloropyrimidin-2-yl)acetate (8.1 g.), mp. 127° to 128° C.

I.R. ν_(max) ^(Nujol) : 3250-3400, 1700, 1650, 1520-1580, 1320,1160-1210, 860, 840 cm⁻¹.

(2) Ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (oil) wasobtained according to the similar manner to that of the Preparation4-(1).

I.R. ν_(max) ^(Film) : 2800-3600, 1680-1730, 1560, 1140-1190, 1020 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.30 (3H, t, J=8 Hz), 3.92 (2H, s), 1.23 (2H, q,J=8 Hz), 8.3-9.3 (1H, broad), 9.4-10.4 (2H, broad).

(3) To a solution of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate(2.3 g.) and sodium acetate (0.93 g.) in 80% ethanol (50 ml.) was added10% palladium on carbon (0.2 g.), and the mixture was stirred under ahydrogen atmosphere for 8 hours at ambient temperature. The reactionmixture was filtered and the filtrate was concentrated. To the residuewere added ethyl acetate and a small amount of water and the ethylacetate layer was separated. The remaining aqueous layer was extractedwith ethyl acetate. The ethyl acetate layers were combined together,washed with water and dried over magnesium sulfate and then the solventwas distilled off. Thus obtained oily substance (2.2 g.) was purified bycolumn chromatography on silica gel (40 g.) using a mixture of benzeneand ethyl acetate as an eluent to give a pale brown solid of ethyl2-(4-formamidopyrimidin-2-yl)acetate (1.3 g.), mp. 80° to 93° C.

I.R. ν_(max) ^(Nujol) : 1710, 1670, 1530, 1310, 1170, 840 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.23 (3H, t, J=8 Hz), 3.78 (2H, s), 4.33 (2H, q,J=8 Hz), 6.5-8.3 (1H, broad), 8.37 (1H, d, J=5 Hz), 9.15 (1H, broad s),9.45 (1H, broad s).

(4) To a solution of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (7.0 g.)in acetic acid (34 ml.) was added dropwise a solution of sodium nitrite(4.1 g.) in water (12 ml.) over a 15 minutes period with stirring at 10°C., and the stirring was continued at the same temperature for an hourand at ambient temperature for another an hour. After cooling thereaction mixture in an ice bath, water (50 ml.) was added thereto. Theprecipitates were collected by filtration and washed successively withwater and diethyl ether and then dried to give a quantitative yield of apowder of ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate, mp.164° to 180° C. (dec.).

N.M.R. δppm (DMSO-d₆): 1.30 (3H, t, J=8 Hz), 4.40 (2H, q, J=8 Hz), 7.5(1H, broad), 8.73 (1H, d, J=6 Hz), 9.05 (1H, broad s).

(5) Ethyl 2-(4-formamidopyrimidin-2-yl)-2-hydroxyiminoacetate (7.0 g.)was dissolved in dioxane (200 ml.) under heating and the resultantsolution was cooled to ambient temperature in an ice bath, and thenthereto was added a solution of diazomethane in diethyl ether withstirring until complete consumption of the starting materials. Thereaction mixture was concentrated to give a brown oil, which waspurified by column chromatography on silica gel (140 g.) using benzeneas an developing solvent and a mixture of benzene and ethyl acetate(3:1) as an eluent to give a pale brown semisolid of ethyl2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.4 g.).

I.R. ν_(max) ^(Film) : 3500-3600 (shoulder), 2900-3400, 1680-1740, 1560,1500, 1250, 1020, 840 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.40 (3H, t, J=8 Hz), 4.17 (3H, s),4.47 (2H, q, J=8Hz), 7.5-8.6 (1H, broad), 8.73 (1H, d, J=6 Hz), 8.9 (1H, broad).

(6) A mixture of ethyl2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (4.3 g.) and 10 Naqueous solution of sodium hydroxide (6.1 ml.) in ethanol (100 ml.) wasstirred for 3 hours at ambient temperature. To the reaction mixture wasgradually added concentrated hydrochloric acid with stirring, wherebysaid mixture was adjusted to pH 3. The precipitates were collected byfiltration and washed successively with ethanol and diethyl ether andthen dried to give white crystals of2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid.

I.R. ν(Nujol): 2500-3300, 1550-1650, 1240, 1000-1040 cm⁻¹.

N.M.R. δppm (D₂ O-N_(a) HCO₃): 4.05 (3H, s), 6.67 (1H, d, J=6 Hz), 8.18(1H, d, J=6 Hz).

The filtrate and washings are combined together and the solvents weredistilled off. The residue was pulverized in diethyl ether, collected byfiltration and then dried to give further the same compound.

(7) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (brownpowder), mp. 64° to 70° C. (dec.) was obtained according to the similarmanner to that of the Preparation 4-(1).

N.M.R. δppm (DMSO-d₆): 4.02 (3H, s), 7.1-7.9 (1H, broad) 8.73 (1H, d,J=6 Hz), 8.9 (1H, broad).

Preparation 9

(1) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (2.95 g.),selenium dioxide (1.73 g.) in dimethylsulfoxide (30 ml.) was stirredunder heating at 50° to 52° C. for an hour and at 70° to 72° C. foranother 0.5 hours. The reaction mixture was cooled to ambienttemperature and filtered, and then the filtered precipitates were washedwith ethyl acetate. The filtrate and washings were combined together andconcentrated to the volume of about 5 ml. under reduced pressure below100° C. The residue was poured into water (50 ml.), and the mixture wasstirred for 10 minutes. The resultant mixture was filtered and thefiltered precipitates were washed with water. The filtrate and washingswere combined together and adjusted to pH 7 with an aqueous solution ofsodium bicarbonate. The mixture was washed with ethyl acetate andsaturated with sodium chloride and then extracted with a mixture ofethyl acetate and ethanol (2:1). The extract was washed with a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate andthen the solvent was distilled off to give a deep yellow oil of amixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and itsmonohydrate, i.e. ethyl2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate (2.4 g.).

(2) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)acetate (2.95 g.),selenium dioxide (1.87 g.) and N,N-dimethyl formamide (15 ml.) wasstirred for an hour under heating at 70° C. The reaction mixture wascooled to ambient temperature and filtered and then the filteredprecipitates were washed with a small amount of N,N-dimethylformamide.The filtrate and washings were combined together and the solvent wasdistilled off. The residue was poured into water (60 ml.) and theresulting mixture was stirred for 10 minutes. The mixture was adjustedto pH 6 to 7 with an aqueous solution of sodium bicarbonate and filteredto separate insoluble substances, which were washed with water. Thefiltrate and washings were combined together and washed successivelywith diethyl ether and ethyl acetate. The aqueous mixture was saturatedwith sodium chloride and then extracted with a mixture of chloroform andethanol (1:1) (60 ml.×4). The extract was dried over magnesium sulfateand the solvent was distilled off. The resulting oily substance (2.2 g.)was dissolved in ethyl acetate (10 ml.) and subjected to columnchromatography on silica gel (15 g.) using ethyl acetate as an eluent.The eluates containing the desired compound were collected and then thesolvent was distilled off. The resulting oily substance (1.5 g.) wasdissolved in a small amount of ethyl acetate and then crystallized fromdiisopropyl ether to give pale yellow crystals of a mixture of ethyl2-(4-formamidopyrimidin-2-yl)glyoxylate and its monohydrate, i.e. ethyl2-(4-formamidopyrimidin-2-yl)-2,2-dihydroxyacetate (0.6 g.), mp. 74° to78° C.

I.R. ν_(max) ^(Nujol) : 3200-3400, 1755, 1690-1710, 1595, 1580, 1280,1250, 1215, 1135, 1100, 1030, 850 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.16 (1.8H, t, J=7 Hz), 1.26 (1.2H, t, J=7 Hz),4.10 (1.2H, q, J=7 Hz) 4.42 (0.8H, q, J=7 Hz), 6.97 (1.2H, broad s),7.0-7.8 (1H, m), 8.64 (0.6H, d, J=6 Hz), 8.90 (0.4H, d, J=6 Hz), 8.8-9.6(1H, m), 11.15 (1H, broad s).

(3) A mixture of ethyl 2-(4-formamidopyrimidin-2-yl)glyoxylate and itsmonohydrate obtained in Preparation 6-(1) was dissolved in ethanol (30ml.) and thereto was added dropwise 1 N ethanol solution of potassiumhydroxide (11 ml.) under ice-cooling with stirring, and then stirringwas continued for 2 hours at ambient temperature. The reaction mixturewas filtered and the filtered precipitates were washed successively witha small amount of ethanol and diethyl ether and then dried to give abrown powder of potassium 2-(4-aminoprimidin-2-yl)glyoxylate (0.4 g.).The filtrate and washings were combined together and concentrated to thevolume of about 15 ml, and to the residue was added diethyl ether (20ml.). The precipitates were collected by filtration and washedsuccessively with a small amount of ethanol and diethyl ether to givefurther a pale brown powder of a mixture of potassium2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate (0.8 g.).

Total yield: 1.2 g.

I.R. ν_(max) ^(Nujol) : 3380, 3200, 1715, 1665, 1600, 1245, 940, 750cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (D.sub.2 O):                                                               6.54 (d, J = 6Hz)                                                                                 (1H)                                                      6.74 (d, J = 6Hz)                                                             8.13 (d, J = 6Hz)                                                                                 (1H)                                                      8.24 (d, J = 6Hz)                                             ______________________________________                                    

(4) To a solution of O-methylhydroxylamine hydrochloride (0.25 g.) inmethanol (6 ml.) was added a mixture of potassium2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring atambient temperature, and the mixture was stirred for 4 hours. Thereaction mixture was allowed to stand overnight at ambient temperature,filtered, and the filtered precipitates were washed with ethanol. Afterthe filtrate and washings were combined together, the solvents weredistilled off. The resultant oily substance was pulverized in acetone(15 ml.) and collected by filtration. Thus obtained powder was washedsuccessively with acetone and diethyl ether and then dried to give apale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (290 mg.).

I.R. ν_(max) ^(Nujol) : 3100-3400, 2500-2900, 1540-1660, 1250, 990-1040cm⁻¹.

N.M.R. δppm (D₂ O+NaHCO₃): 4.05 (3H, s), 6.63 (1H, d, J=6 Hz), 8.13 (1H,d, J=6 Hz).

Preparation 10

(1) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)acetate (crystal) wasobtained according to the similar manner to that of the Preparation4-(1).

I.R. ν_(max) ^(Nujol) : 3200, 3140, 1730, 1700, 1540-1580, 1500, 1420,1380, 1350, 1270, 1240, 1140, 840, 770, 740 cm⁻¹.

(2) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)2-hydroxyiminoacetate,mp. 110° to 112° C. was obtained according to the similar manner to thatof the Preparation 8-(4).

I.R. ν_(max) ^(Nujol) : 3200, 1740, 1700, 1675, 1570, 1560, 1380, 1270,1240, 1180, 1045, 860, 810, 750 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.90 (3H, s), 7.57 (1H, s) 9.23 (1H, d, J=9 Hz),11.40 (1H, d, J=9 Hz), 13.28 (1H, s).

(3) Methyl 2-(2-formamido-6-chloropyrimidin-4-yl)2-methoxyiminoacetate(powder), mp. 165° to 172.5° C. was obtained according to the similarmanner to that of the Preparation 8-(5).

I.R. ν_(max) ^(Nujol) : 3150, 1750, 1700, 1670, 1645, 1420, 1380, 1270,1250, 1040, 955, 795, 735 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.93 and 4.14 (6H, s), 7.59 (1H, s), 9.26 (1H, d,J=9 Hz), 11.50 (1H, d, J=9 Hz).

(4) 2-(2-Amino-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid(powder) was obtained according to the similar manner to that of thePreparation 8-(6).

I.R. ν_(max) ^(Nujol) : 3350, 3200, 1695-1740, 1660, 1365, 1030 cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6 + D.sub.2 O):                                                    3.80 (3H, s),                                                                 6.16 (s)                                                                                        (1H)                                                        6.77 (s)                                                  ______________________________________                                    

(5) 2-(2-Formamido-6-chloropyrimidin-4-yl)-2-methoxyiminoacetic acid(powder), mp. 138° to 142° C. (dec.) was obtained according to thesimilar manner to that of Preparation 4-(1).

I.R. ν_(max) ^(Nujol) : 3400, 3325, 3200, 1740, 1695, 1670, 1550, 1385,1250, 1040, 820 cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6):                                                            4.05 (3H, s)                                                                  6.87 (s)                                                                                            (1H)                                                    6.93 (s)                                                                      9.38 (1H, d, J = 9Hz)                                                         11.11 (1H, d, J = 9Hz)                                        ______________________________________                                    

Preparation 11

(1) A 15% n-hexane solution (636 g.) of n-butyllithium was added to asolution of 2-amino-6-methylpyridin (64.8 g.) in tetrahydrofuran (500ml.) at -20° to -30° C. over one hour, and stirred at -8° to -10° C. for30 minutes. To the solution was added trimethylsilylchloride (161.7 g.)at -15° to -5° C. over 40 minutes, and the resultant solution wasstirred at room temperature overnight. The solution was filtered throughby a column packed with silica gel (180 g.), washed with tetrahydrofuranand then the filtrate was concentrated under reduced pressure. Theresidue was purified by fractional distillation to give a2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (117.6 g.), b.p. 95°to 97° C./5-6 mmHg.

N.M.R. δppm (CCl₄): 0.13 (18H, s), 2.35 (3H, s), 6.43 (1H, d, J=8 Hz),6.60 (1H, d, J=8 Hz), 7.25 (1H, s, J=8 Hz).

(2) A 15% n-hexane solution (338.6 g.) of n-butyllithium was dropwiseadded to a solution of 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine(100 g.) in anhydrous tetrahydrofuran (300 ml.) at -20° to -30° C. overone hour and the solution was stirred at 20° to 23° C. for one hour. Theresultant solution was added in small portions to crushed dry ice (1kg.) under stirring, and stirred till a room temperature. After removingtetrahydrofuran from the solution under reduce pressure, absoluteethanol (1 l.) was added to the residue. 30% Ethanol solution (660 ml.)of hydrochloric acid was dropwise added to the solution at -5° to -10°C., and further hydrogen chloride gas was bubbled at 0° to 5° C. for 30minutes and then the solution was stirred at 10° C. overnight. Afterremoving ethanol from the resultant solution, the residue was dissolvedin water, and washed with ethyl acetate 3 times. The solution wasadjusted to pH 7 to 8 with sodium bicarbonate and extracted with ethylacetate. The ethyl acetate extract was washed with a saturated aqueoussolution of sodium chloride, dried and concentrated under reducedpressure to give the crude product (54 g.). The product was purified bycolumn chromatography on silica gel (1 kg.) with an eluent (ethylacetate+benzene) to give ethyl 2-(6-aminopyridin-2-yl)acetate (30.2 g.),mp. 66° to 68° C.

I.R. ν_(max) ^(Nujol) : 3430, 3340, 3200, 1730, 1645, 1480, 1190 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.25 (3H, t, J=6 Hz), 3.67 (2H, s), 4.20 (2H, q,J=6 Hz), 5.33 (2H, broad s), 6.43 (1H, d, J=8 Hz), 6.62 (1H, d, J=8 Hz),7.40 (1H, t, J=8 Hz).

(3) Ethyl 2-(6-formamidopyridin-2-yl)acetate, mp. 35° to 38° C. wasobtained according to the similar manner to that of the Preparation4-(1).

I.R. ν_(max) ^(Nujol) : 3250, 3100, 1738, 1690, 1580, 1460, 1305, 1277cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.17 (3H, t, J=8 Hz), 3.75 (2H, s), 4.08 (2H, q,J=8 Hz), 6.85 (0.5H, broad d, J=8 Hz), 7.95 (0.5H, broad s), 7.08 (1H,d, J=8 Hz), 7.73 (1H, t, J=8 Hz), 8.33 (0.5H, broad s), 9.25 (0.5H,broad d), 10.58 (1H, broad s).

(4) To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (26 g.) indioxane (260 ml.) was added selenium dioxide (16.65 g.) in smallportions at 85° to 90° C. over one hour and stirred at the sametemperature for one hour. After cooling the resultant solution thedioxane layer was separated and concentrated under reduced pressure andthen the residue was dissolved in ethyl acetate. The solution was washedwith water, dried over magnesium sulfate and treated with activatedcharcoal and then concentrated under reduced pressure. The residue wastriturated with diethyl ether to give ethyl2-(6-formamidopyridin-2-yl)glyoxylate (14.3 g.), mp. 124° to 126° C.

I.R. ν_(max) ^(Nujol) : 3220, 3100, 1737, 1720, 1690, 1273, 1233 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.34 (3H, t, J=8 Hz), 4.44 (2H, q, J=8 Hz), 7.33(0.65H, broad s), 7.8-8.2 (0.35H), 7.84 (1H, d, J=8 Hz), 8.09 (1H, t,J=8 Hz), 8.44 (0.35H, broad s), 9.22 (0.65H, broad s), 10.85 (1H, broads).

(5) 2-(6-Formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer),mp. 170° to 171° C. (dec.) was obtained according to the similar mannerto that of the Preparation 4-(4) via2-(6-formamidopyridin-2-yl)glyoxylic acid.

I.R. ν_(max) ^(Nujol) : 3230, 3132, 1745, 1680, 1575, 1450, 1320, 1208,1032 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.70 (3H, s), 6.90 (0.6H, broad d), 7.9 (0.4H,broad s), 7.10 (1H, d, J=8 Hz), 7.75 (1H, t, J=8 Hz), 8.38 (0.4H, broads), 9.25 (0.6H, broad d), 10.58 (1H, broad d).

(6) A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (5.0 g.) and concentrated hydrochloric acid (2.34 g.) inmethanol (50 ml.) was stirred for 40 minutes at ambient temperature.After the removal of methanol from the reaction mixture under reducedpressure, the residue was pulverized in diethyl ether, collected byfiltration and then dried to give a pale brown powder of2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloric (synisomer) (5.2 g.).

N.M.R. δppm (DMSO-d₆ +D₂ O): 4.10 (3H, s), 6.84 (1H, d, J=7 Hz), 7.23(1H, d, J=10 Hz), 7.99 (1H, dd, J=7 Hz, 10 Hz).

(7) To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acidhydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) wasintroduced chloride gas for 1.5 hours. After the removal of the excessof the chlorine gas by bubbling air into the reaction mixture, thesolvent was distilled off. The residue was pulverized in diethyl etherand collected by filtration. After the addition of water and ethylacetate to the resultant powder (9.8 g.), the aqueous layer wasseparated and washed with ethyl acetate. The ethyl acetate layer andwashings were combined together, and further extracted with water. Theaqueous layers were combined together and adjusted to pH 4 with 1 Naqueous solution of sodium hydroxide, and then the solvent was distilledoff under reduced pressure. The remaining water in the residue wasazeotropically removed with benzene three times to yield brownish powderwhich was dried in a desiccator to give2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer)(3.27 g.).

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.81 (3H, s), 6.50 (1H, d, J=9 Hz), 7.48(1H, d, J=9 Hz).

Further the remaining ethyl acetate layer was dried over magnesiumsulfate and the solvent was distilled off. The residue was washed withdiethyl ether and then dried to give2-(6-amino-3,5-dichloropyridin-2-yl)-2-methoxyiminoacetic acid (synisomer) (2.4 g.), mp. 139° to 144° C.

N.M.R. δppm (DMSO-d₆): 3.96 (3H, s), 6.2-7.1 (2H, broad), 7.83 (1H, s).

(8)-a) 2-(3-Chloro-6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (powder), mp. 151° to 154° C. was obtained according to thesimilar manner to that of the Preparation 4-(1).

I.R. ν_(max) ^(Nujol) : 3200, 1740, 1680, 1580, 1290, 1250, 1140, 1050,840 cm⁻¹.

(8)-b) 2-(3,5-Dichloro-6-formamidopyridin-2-yl)-2-methoxyiminoaceticacid (syn isomer) (powder), mp. 164° to 165° C. was obtained accordingto the similar manner to that of the Preparation 4-(1).

I.R. ν_(max) ^(Nujol) : 3250, 2300-2600, 1712, 1565, 1410, 1250, 1035cm⁻¹.

N.M.R. δppm (DMSO): 4.02 (3H, s), 8.29 (1H, s), 9.05 (1H, d, J=10 Hz),10.77 (1H, d, J=10 Hz).

Preparation 12

To a solution of ethyl 3-ethoxyacrylimidate hydrochloride (4.0 g) and1-ethoxycarbonylformamidine hydrobromide (4.4 g) in methanol (110 ml)was added dropwise a solution of sodium metal (1 g) in methanol (110 ml)at 0° C. The reaction mixture was stirred for an hour at 0° to 5° C. andfor additional 4 hours at ambient temperature. The solution wasevaporated to dryness and the residue was dissolved in a mixture ofethyl acetate and an aqueous solution of sodium chloride. The organiclayer was separated out and the aqueous layer was extracted with ethylacetate five times. All organic layers were combined, dried overanhydrous magnesium sulfate and evaporated to dryness. The residue wastriturated with diethylether to give methyl4-aminopyrimidine-2-carboxylate (1.33 g), which was recrystallized fromethyl acetate, mp. 140°-142.5° C.

I.R. ν_(max) ^(Nujol) : 3450, 3300, 3180, 1730, 1630, 1585, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.81 (3H,S), 6.54 (1H,d,J=6 Hz), 7.23 (2H,S),8.16 (1H,d,J=6 Hz).

Preparation 13

(1) To a solution of 2-chloroacrylonitrile (437 mg) and1-ethoxycarbonylformamidine hydrobromide (985 mg) in ethanol (5 ml) wasadded dropwise triethylamine (1.01 g) at 0° C. The reaction mixture wasstirred for 4 hours at ambient temperature and evaporated to dryness.The residue was dissolved in a mixture of ethyl acetate and water, andextracted with ethyl acetate three times. The combined extracts weredried over anhydrous magnesium sulfate and evaporated to dryness. Theresidue was triturated with diethyl ether to give ethyl4-aminopyrimidine-2-carboxylate (480 mg), which was recrystallized froma mixture of ethyl acetate and benzene, mp. 101°-104° C.

I.R. ν_(max) ^(Nujol) : 3450, 3300, 3180, 1730, 1630, 1580, 1540 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (3H,t,J=7 Hz), 4.30 (2H,q,J=7 Hz), 6.60(1H,d,J=6 Hz), 7.31 (2H, S), 8.20 (1H, d, J=6 Hz).

The following compound was obtained according to the similar manner tothat of Preparation 13-(1) by using triethylamine or sodium carbonate asa base.

(2) Methyl 4-aminopyrimidine-2-carboxylate.

I.R. ν_(max) ^(Nujol) : 3450, 3300, 3180, 1730, 1630, 1585, 1540 cm⁻¹.

Preparation 14

(1) A mixture of formic acid (100 g) and acetic anhydride (204 g) wasstirred for half an hour at ambient temperature. To the solution wasadded ethyl 4-aminopyrimidine-2-carboxylate (30 g) and the mixture wasstirred for 1.5 hours at 70° to 75° C. and then evaporated to dryness.The residue was triturated with ethanol, collected by filtration andwashed with ethanol to give ethyl 4-formamidopyrimidine-2-carboxylate(20.0 g), mp 205°-206° C.

I.R. ν_(max) ^(Nujol) : 3100, 1720, 1630, 1570, 1520 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.37 (3H,t,J=7 Hz), 4.40 (2H,q,J=7 Hz), 7.73 (1H,broad s), 8.83 (1H, d,J=4 Hz), 9.00 (1H,broad s), 11.40 (1H, broad s).

The following compound was obtained according to the similar manner tothat of Preparation 14-(1).

(2) Methyl 4-formamidopyrimidine-2-carboxylate, mp 234°-236° C.

I.R. ν_(max) ^(Nujol) : 3100, 1735, 1710, 1640, 1570, 1530, 1510 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 3.93 (3H,s), 7.73 (1H, broad s), 8.82 (1H,d,J=5Hz), 9.00 (1H, broad s), 11.40 (1H, broad s).

Preparation 15

(1) To a solution of methyl 4-formamidopyrimidine-2-carboxylate (1.3 g)and methyl methylthiomethyl sulfoxide (0.89 g) in N,N-dimethylformamide(10 ml) was added 50% sodium hydride (1.0 g) at 10° C. under stirringand the stirring was continued for 1.5 hours at ambient temperature. Themixture was cooled in an ice bath and thereto was added methylenechloride (30 ml).

The precipitate which was collected by filtration was added portionwiseto a mixture of methylene chloride (50 ml), ice water and concentratedhydrochloric acid (2.1 ml) under stirring. The methylene chloride layerwas separated out and the aqueous layer was extracted with methylenechloride. The combined extracts were dried over anhydrous magnesiumsulfate and evaporated to dryness. The residue was triturated withdiethyl ether, filtered and washed with diethyl ether to give4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl) pyrimidine (1.2 g).

I.R. ν_(max) ^(Nujol) : 1690, 1560, 1450, 1370 cm⁻¹.

    ______________________________________                                        N.M.R. δ ppm (DMSO-d.sub.6):                                                                2.23 (s)                                                                                      (3H),                                                         2.30 (s)                                                  2.73 (s)                  5.95 (s)                                                             (3H),                  (1H),                                 2.93 (s)                  6.07 (5)                                            7.67 (1H, broad s), 8.92 (1H,d,J = 5Hz), 9.17 (1H,                            broad s), 11.40 (1H, broad s)                                                 ______________________________________                                    

The same compound as the object compound of Preparation 15-(1) wasobtained from the following compound according to the similar mannerthereto.

(2) Ethyl 4-formamidopyrimidine-2-carboxylate.

Preparation 16

A mixture of formic acid (4.82 g) and acetic anhydride (9.7 g) wasstirred for half an hour at ambient temperature.

To the solution was added4-formamido-2-(2-methanesulfinyl-2-methylthioacetyl)pyrimidine (2.6 g)and the mixture was stirred for 1.5 hours at 50° C. and then for an hourwith an addition of sodium periodate (610 mg) at the same temperature.The mixture was evaporated to dryness and the residue was dissolved in amixture of ethyl acetate (50 ml) and an aqueous solution (20 ml) ofsodium chloride. The organic layer was separated out and the aqueouslayer was extracted with ethyl acetate three times. The combined organiclayers were dried over anhydrous magnesium sulfate and evaporated todryness. The residue (2.0 g) was subjected to column chromatography oversilica gel (13 g) using a mixture of ethyl acetate and benzene (1:1 byvolume) as an eluent. The fractions containing a desired compound werecollected, evaporated to dryness and crystallized from a small amount ofethyl acetate to give pure product of S-methyl4-formamidopyrimidine-2-thioglyoxylate (840 mg), mp 112°-114° C.

I.R. ν_(max) ^(Nujol) : 3480, 3380, 1715, 1680, 1585 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 2.17 (3H,s), 7.20 (1H, broad s), 8.12 (1H,d,J=6Hz), 9.17 (1H, broad s), 11.08 (1H,d,J=7 Hz).

Preparation 17

(1) To a suspension of S-methyl 4-formamidopyrimidine-2-thioglyoxylate(3.0 g) in water (26 ml) was added dropwise 1 N aqueous solution (12 ml)of sodium hydroxide at ambient temperature and the mixture was stirredfor half an hour at the same temperature.

To the solution was added an aqueous solution of ethoxyamine prepared byethoxyamine hydrochloride (1.3 g), water (10 ml) and sodium bicarbonate(1.12 g). The reaction mixture was stirred for half an hour at ambienttemperature and adjusted to pH 4 with 1 N hydrochloric acid (1.5 ml).The solution was stirred for 10 minutes at ambient temperature andadjusted to pH 3 with 1 N hydrochloric acid and then washed with ethylacetate. The aqueous layer was salted out, adjusted to pH 1 with 10%hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated to dryness. Th crystallizedresidue was washed with n-hexane to give2-ethoxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (syn isomer)(2.22 g), mp. 130°-135° C.(dec.).

I.R. ν_(max) ^(Nujol) : 3250, 1720, 1630, 1605, 1570 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.28 (3H,t,J=7 Hz), 4.32 (2H,q,J=7 Hz), 7.4-7.7(1H, m), 8.72 (1H,d,J=6 Hz), 8.8-9.1 (1H, m), 11.37 (1H,d,J=6 Hz).

The following compounds were obtained according to the similar manner tothat of Preparation 17-(1).

(2) 2-(4-Formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (synisomer), mp. 165°-166° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3400, 3250, 3150, 1740, 1700, 1570 cm⁻¹.

N.M.R. δppm (DMSO-d₆): 4.00 (3H,s), 7.53 (1H, broad s), 8.72 (1H,d, J=6Hz), 8.87 (1H,broad s), 11.23 (1H,d,J=6 Hz).

(3) 2-(4-Formamidopyrimidin-2-yl)-2-propoxyiminoacetic acid (synisomer), mp 145°-148° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3150, 3100, 3050, 1750, 1690, 1615, 1570, 1540cm⁻¹.

(4) 2-Allyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (synisomer), mp 120°-122° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3250, 3100, 1710, 1630, 1570, 1515 cm⁻¹.

(5) 2-Benzyloxyimino-2-(4-formamidopyrimidin-2-yl)acetic acid (synisomer), mp 75°-77° C.

I.R. ν_(max) ^(Nujol) : 3250, 3050, 1720, 1630, 1570 cm⁻¹.

Preparation 18

A mixture of ethyl 2-(6-chloro-4-formamidopyrimidin-2-yl)acetate (24.3g) and selenium dioxide (16.65 g) in N,N-dimethylformamide (243 ml) wasstirred for an hour at 70° to 75° C. The precipitated solid was filteredoff, and the filtrate was concentrated in vacuo. The residue wasdissolved in ethyl acetate (500 ml), washed with water and an aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andevaporated to dryness. The residue was triturated with diisopropyl etherto give a powder of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate(17.74 g).

This product (1 g) was recrystallized from ethyl acetate (10 ml) toafford the purified product (570 mg), mp 114°-117° C.

I.R. ν_(max) ^(Nujol) : 3400, 3230-3100, 1760, 1720-1680, 1580-1550,1250, 1200, 850, 730 cm⁻¹.

Preparation 19

To a mixture of ethyl 6-chloro-4-formamidopyrimidin-2-ylglyoxylate (10.6g) and methoxyamine hydrochloride (3.34 g) in ethanol (200 ml) was addedan aqueous solution (60 ml) of sodium bicarbonate (3.36 g) and themixture was stirred for 2 hours at ambient temperature. Afterevaporation of the solvent, the residue was dissolved in ethyl acetate.The solution was washed with water, dried over anhydrous magnesiumsulfate and evaporated to give oily product (10.8 g).

This product was subjected to column chromatography over silica gel (118g) using benzene as an eluent. The fractions contained a desiredcompound were collected, and evaporated, and the resultant oily product(5.6 g) was crystallized from diethyl ether to give ethyl2-(6-chloro-4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (synisomer), mp. 116°-119° C.

I.R. ν_(max) ^(Nujol) : 3400, 1750, 1725, 1665, 1495, 1270, 1030 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.35 (3H,t,J=7 Hz), 4.09 (3H, s), 4.40 (2H,q,J=7Hz), 6.5-8.3 (1H, broad), 8.3-9.0 (1H,broad), 9.2 (1H, broad s).

Preparation 20

A mixture of ethyl 2-(4-formamidopyrimidine-2-yl) acetate (50.0 g) andselenium dioxide (31.87 g) in N,N-dimethylformamide (240 ml) was stirredfor an hour at 70° to 75° C. and cooled to ambient temperature. Theprecipitated solid was filtered off and the filtrate was evaporated invacuo to give an oily product. The oil was added to water (750 ml) understirring, adjusting to pH7 with an aqueous solution of sodiumbicarbonate. The precipitated yellow substance was filtered off andwashed with water. The filtrate and washings were combined and theretowas added methoxyamine hydrochloride (19.95 g). The mixture was adjustedto pH4 with an aqueous solution of sodium bicarbonate and stirred for 3hours at ambient temperature. The aqueous reaction mixture was extractedwith ethyl acetate and the extract was washed with an aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate andevaporated to give ethyl2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (31 g)as a brownish oil.

N.M.R. δppm (CDCl₃): 1.36 (3H,t,J=7 Hz), 4.12 (3H,s), 4.42 (2H,q,J=7Hz), 6.5-8.2 (1H, broad), 8.66 (1H,d,J=6 Hz), 8.8-10.0 (2H, broad).

Preparation 21

(1) To a solution of ethyl2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer)(30.8 g) in ethanol (308 ml) was added 1 N alcoholic solution (550 ml)of potassium hydroxide and the mixture was stirred for 3.5 hours atambient temperature. The reaction mixture was cooled in an ice bath andadjusted to pH 3 with concentrated hydrochloric acid (53 ml). Theresultant solid was filtered and washed with ethanol (60 ml), water (100ml), acetone (100 ml) to give a crude product (28.8 g). This product (1g) was recrystallized from water (10 ml) to give a purified product of2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (dihydrate, synisomer) (0.4 g), mp. 178°-183° C. (dec.). The following compound wasobtained according to the similar manner to that of Preparation 21-(1).

(2) 2-(4-Amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetic acid (synisomer).

I.R. ν_(max) ^(Nujol) : 3480, 3380, 3200, 1640, 1610-1580, 1530, 1040,720 cm⁻¹.

N.M.R. δppm (D₂ O): 4.10 (3H,s), 6.76 (1H,s).

Preparation 22

To a solution of ethyl2-(4-chloro-6-formamidopyrimidin-2-yl)-2-methoxyiminoacetate (synisomer) (17 g) in ethanol (255 ml) was added dropwise phosphorylchloride (14.7 g) under cooling in an ice bath. The mixture was stirredfor 1.5 hours at ambient temperature and evaporated to dryness.

The residue was dissolved in a mixture of ethyl acetate and water andadjusted to pH 7 with an aqueous solution of sodium bicarbonate. Theorganic layer was separated out, dried over anhydrous magnesium sulfateand evaporated to dryness. The residue was triturated with n-hexane togive ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (synisomer) (9.99 g), mp 136°-142° C.

I.R. ν_(max) ^(KBr) : 3500, 3380, 3200, 1735, 1640, 1575, 1535, 1040cm⁻¹.

N.M.R. δppm (DMSO-d₆): 1.30 (3H,t,J=7 Hz), 4.03 (3H,s), 4.30 (2H,q,J=7Hz), 6.53 (1H,s), 7.5 (2H, broad s).

Preparation 23

(1) To a solution of ethyl 2-(4-amino-6-chloropyrimidin-2-yl)acetate(21.5 g) in methanol (200 ml) was added a solution of sodium metal (7.25g) in methanol (130 ml) and the mixture was refluxed for 3.5 hours. Thereaction mixture was cooled in an ice-salt bath and saturated with dryhydrogen chloride and then allowed to stand overnight at ambienttemperature. The mixture was evaporated to dryness and the residue wasdissolved in a mixture of ethyl acetate and a cold aqueous solution ofsodium bicarbonate. The organic layer was separated out, washed withwater, dried over anhydrous magnesium sulfate and and evaporated to givemethyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate (14.2 g), mp 91°-94°C.

I.R. ν_(max) ^(Nujol) : 3480, 3390, 3210, 1738, 1660, 1600 cm⁻¹.

N.M.R. δppm (DMSO-d6): 3.66 (5H, s), 3.82(3H, s), 5.68 (1H, s), 6.66(2H, broad s).

(2) To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bathand the mixture was stirred for 20 minutes at 0° C. to 5° C. To themixture was added ethyl2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and themixture was stirred for 6 hours at ambient temperature. The resultantmixture was poured into cold water, adjusted to pH 7 with dilutedhydrochloric acid and extracted with ethyl acetate. The extract waswashed with water, dried over anhydrous magnesium sulfate and evaporatedto dryness. The residue was subjected to column chromatography on silicagel (50 g) using a mixture of chloroform and ethyl acetate (3:1 byvalume) as an eluent. The fractions containing the object product werecollected and evaporated to give ethyl2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (synisomer) (460 mg), mp 154°-156° C.

I.R. ν_(max) ^(Nujol) : 3450, 3280, 3160, 1720, 1620, 1550, 1520, 1300,1040, 1025, 700 cm⁻¹.

N.M.R. δppm (CDCl₃): 1.34 (3H, t, J=7 Hz), 4.05 (3H, s), 4.27 (2H, q,J=7 Hz) 5.2 (2H, broad s), 5.84 (1H, s), 7.2-7.7 (5H, m).

Preparation 24

Methyl 2-(4-formamido-6-methoxypyridin-2-yl)acetate (13.9 g) wasobtained by reacting methyl 2-(4-amino-6-methoxypyrimidin-2-yl)acetate(14 g) with formic acid (14.7 g) and acetic anhydride (30.4 g) accardingto the similar manner to that of Preparation 14-(1), mp 61°-63° C.

N.M.R. δppm (DMSO-d6): 3.73 (3H, s), 3.87 (2H, s), 3.96 (3H, s), 6.1-7.8(1H, broad), 8.1-9.8 (1H, broad), 10.87 (1H, d, J=6 Hz).

Preparation 25

Methyl 2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate(syn isomer) (12.47 g) was obtained by reacting methyl2-(4-formamido-6-methoxypyrimidin-2-yl)acetate (12.24 g) with seleniumdioxide (6.94 g) and then methoxyamine hydrochloride (4.51 g) accordingto the semilar manner to that of Preparation 20,

I.R. ν_(max) ^(Film) : 3300, 1750, 1720, 1660, 1590, 1565, 1210, 1035cm⁻¹.

Preparation 26

(1) 2-(4-Amino-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetic acid (synisomer) (8.22 g) was obtained by reacting methyl2-(4-formamido-6-methoxypyrimidin-2-yl)-2-methoxyiminoacetate (synisomer) (12.0 g) with 1 N ethanolic solution (187 ml) of potassiumhydroxide according to the similar manner to that of Preparation 21, mp127°-129° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3420, 3380, 1650, 1615, 1590, 1250, 1050, 1025cm⁻¹.

N.M.R. δppm (DMSO-d₆ +D₂ O): 3.78 (3H,s), 3.95 (3H,s), 5.78 (1H,s).

(2) 2-(4-Amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetic acid(syn isomer) (130 mg) was obtained by reacting ethyl2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyimino-acetate (synisomer) (247 mg) with 1 N aqueous solution (1.8 ml) of sodium hydroxideaccording to the similar manner to that of Preparation 21, mp 136°-138°C. (dec.).

I.R. ν_(max) ^(Nujol) : 3300, 1650, 1600, 1560, 1150, 1040, 750 cm⁻¹.

Preparation 27

To a suspension of S-methyl (4-formamidopyrimidin-2-yl)thioglyoxylate(6.7 g) in water (60 ml) was added dropwise 1 N aqueous solution ofsodium hydroxide (26.8 ml) over a period of 15 minutes with stirring,and the stirring was continued at ambient temperature for 20 minutes.

On the other hand, an ethanolic solution (50 ml) of N-phenoxyphthalimide(9.26 g) and hydrazine monohydrate (1.84 g) was refluxed under heatingfor 5 minutes and the precipitates were removed by filtration. Theresultant solution was added to the aqueous solution obtained above,followed by stirring for 5 minutes. After adjusting to pH 3 to 4 with 6N hydrochloric acid, the stirring was continued at ambient temperaturefor additional 3 hours. The ethanol was removed by evaporation from thereaction mixture, and the remaining aqueous solution was adjusted to pH7 to 8 with 5% aqueous solution of sodium bicarbonate and then washedwith ethyl acetate. To the aqueous solution was added ethyl acetate andthen adjusted to pH 1 to 2 with hydrochloric acid. The separated ethylacetate layer was washed with water, dried over magnesium sulfate andevaporated to dryness. The residue was pulverized with diisopropyl etherto give a brownish powder (2.2 g) of2-(4-formamidopyrimidin-2-yl)-2-phenoxyiminoacetic acid (syn isomer), mp131°-133° C. (dec.).

I.R. ν_(max) ^(Nujol) : 3150, 1740, 1680, 1660, 1575, 1540, 1440, 1310,1205, 980, 760 cm⁻¹.

N.M.R. δppm (DMSO-d6): 7.1-7.9 (5H, m), 8.15 (1H, m), 8.97 (1H, d, J=6Hz), 9.23 (1H, m), 11.57 (1H, d, J=6 Hz).

What we claim is:
 1. A compound of the formula: ##STR15## wherein R¹ isa group of the formula: ##STR16## in which R_(a) ¹ is hydrogen, amino ora protected amino group, R_(b) ¹ and R_(c) ¹ are each hydrogen, halogen,lower alkoxy, phenylthio, tolylthio, xylylthio, mesitylthio ornaphthylthio,R² is hydrogen or lower alkoxy, R³ is hydrogen or loweralkyl, R⁴ is hydrogen, halogen, carbamoyloxymethyl, lower alkyl, loweralkoxy, lower alkanoyloxymethyl or lower alkanoylthiomethyl, R⁵ iscarboxy or a protected carboxy group, and X is a group of the formula:##STR17## in which R⁶ is hydrogen, lower alkyl, mono to trihalo (lower)alkyl, lower alkenyl, lower alkynyl, phenyl, tolyl, xylyl, cumenyl,naphthyl, phenyl (lower) alkyl, mono or dihalo (lower) alkanoyl, orlower alkoxy, and non-toxic, pharmaceutically acceptable salts thereof.2. A compound of claim 1, whereinR¹ is a group of the formula: ##STR18##in which R_(a) ¹ is hydrogen, amino or acylamino, R_(b) ¹ and R_(c) ¹are each hydrogen, halogen, lower alkoxy or phenylthio, R² is hydrogenor lower alkoxy, R³ is hydrogen or lower alkyl, R⁴ is hydrogen, halogen,carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl,or lower alkanoylthiomethyl, R⁵ is carboxy or an esterified carboxygroup, and X a group of the formula: ##STR19## in which R⁶ is hydrogen,lower alkyl, trihalo(lower)alkyl, lower alkenyl, lower alkynyl, phenylor phenyl(lower)alkyl.
 3. A compound of claim 2, whereinR¹ is a group ofthe formula: ##STR20## in which R_(a) ¹ is hydrogen, amino, loweralkanoyl or trihalo(lower)alkanoyl, R_(b) ¹ and R_(c) ¹ are eachhydrogen, halogen, lower alkoxy or phenylthio, R² is hydrogen or loweralkoxy, R³ is hydrogen or lower alkyl, R⁴ is hydrogen, halogen,carbamoyloxymethyl, lower alkyl, lower alkoxy, lower alkanoyloxymethyl,or lower alkanoylthiomethyl R⁵ is carboxy,nitrophenyl(lower)alkoxycarbonyl or diphenyl(lower)alkoxycarbonyl, and Xis a group of the formula: ##STR21## in which R⁶ is hydrogen, loweralkyl, trihalo(lower)alkyl, lower alkenyl, lower alkynyl, phenyl orphenyl(lower)alkyl, in which R⁶ is as defined in claim
 3. 4. A compoundof claim 3,wherein R¹ is a group of the formula: ##STR22## in whichR_(c) ¹ is hydrogen, halogen, lower alkoxy or phenylthio and R² ishydrogen.
 5. A compound of claim 4, wherein R⁵ is carboxy.
 6. A compoundof claim 5, whereinR_(c) ¹ is hydrogen, chloro, methoxy or phenylthio,R³ is hydrogen or methyl, R⁴ is hydrogen, chloro, carbamoyloxymethyl,methyl, acetoxymethyl, or acetylthiomethyl, and R⁶ is methyl, ethyl,propyl, allyl, benzyl or phenyl.
 7. A compound of claim 6, which is7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylicacid (syn isomer).
 8. A compound of claim 6, which is7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).
 9. A compound of claim 6, which is7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]cephalosporanicacid (syn isomer).
 10. A compound of claim 6, which is7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).
 11. A compound of claim 3, whereinR¹ is a group ofthe formula: ##STR23## in which R_(a) ¹ is lower alkanoylamino, and R²is hydrogen.
 12. A compound of claim 11, whereinR_(a) ¹ is formamido, R³is hydrogen, R⁴ is acetoxymethyl, R⁵ is carboxy and R⁶ is methyl, ethyl,propyl, allyl or benzyl.
 13. A compound of claim 3, whereinR¹ is a groupof the formula: ##STR24## in which R_(a) ¹ is lower alkanoyl amino andR_(c) ¹ is hydrogen or halogen, and R² is hydrogen.
 14. A compound ofclaim 13, whereinR_(a) ¹ is formamido, R_(c) ¹ is hydrogen or chloro, R³is hydrogen, R⁵ is carboxy and R⁶ is methyl.
 15. An anti-bacterialpharmaceutical composition comprising, as an active ingredient, aneffective amount of the compound of claim 1, in association with anon-toxic, pharmaceutically acceptable carrier or excipient.
 16. Amethod for treating an infectious disease caused by pathogens, whichcomprises administering the compound of claim 1 to infected human beingsand animals.